US9517988B2 - Phenol derivative and preparation method and use in medicine thereof - Google Patents
Phenol derivative and preparation method and use in medicine thereof Download PDFInfo
- Publication number
- US9517988B2 US9517988B2 US14/936,310 US201514936310A US9517988B2 US 9517988 B2 US9517988 B2 US 9517988B2 US 201514936310 A US201514936310 A US 201514936310A US 9517988 B2 US9517988 B2 US 9517988B2
- Authority
- US
- United States
- Prior art keywords
- alkyl
- carbocyclic group
- hydroxyl
- compound
- membered
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title abstract description 10
- 239000003814 drug Substances 0.000 title abstract description 9
- 150000002989 phenols Chemical class 0.000 title abstract description 6
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- 150000003839 salts Chemical class 0.000 claims abstract description 93
- 229940002612 prodrug Drugs 0.000 claims abstract description 80
- 239000000651 prodrug Substances 0.000 claims abstract description 80
- 239000012453 solvate Substances 0.000 claims abstract description 71
- 239000002207 metabolite Substances 0.000 claims abstract description 70
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 383
- 229910052731 fluorine Inorganic materials 0.000 claims description 346
- 125000002837 carbocyclic group Chemical group 0.000 claims description 289
- 229910052794 bromium Inorganic materials 0.000 claims description 276
- 239000000460 chlorine Substances 0.000 claims description 256
- 229910052801 chlorine Inorganic materials 0.000 claims description 254
- 125000000217 alkyl group Chemical group 0.000 claims description 227
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 221
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 217
- 229910052739 hydrogen Inorganic materials 0.000 claims description 213
- 125000001424 substituent group Chemical group 0.000 claims description 183
- -1 cyano, carboxyl Chemical group 0.000 claims description 181
- 125000000623 heterocyclic group Chemical group 0.000 claims description 181
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 174
- 229910052740 iodine Inorganic materials 0.000 claims description 162
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- 229910052717 sulfur Inorganic materials 0.000 claims description 140
- 125000005842 heteroatom Chemical group 0.000 claims description 125
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 112
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- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 28
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 24
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- 150000002500 ions Chemical class 0.000 claims description 15
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- 125000004429 atom Chemical group 0.000 claims description 14
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- 241001465754 Metazoa Species 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 11
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 10
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 claims description 10
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 9
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- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 8
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- 238000000034 method Methods 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 7
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 7
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 6
- 125000004011 3 membered carbocyclic group Chemical group 0.000 claims description 6
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 6
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 6
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 6
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- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 6
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- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 6
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 6
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- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 6
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 6
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- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 6
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- 229940124597 therapeutic agent Drugs 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/094—Esters of phosphoric acids with arylalkanols
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
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- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/242—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of hydroxyaryl compounds
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
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Definitions
- the present invention relates to a phenol derivative represented by general formula (A) or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt or a cocrystal thereof, also to a preparation method thereof, a pharmaceutical composition thereof, and use of the compound of the present invention in the field of central nervous system.
- A phenol derivative represented by general formula (A) or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt or a cocrystal thereof
- the GABA A receptor is a receptor of the chief inhibitory neurotransmitter in the central nervous system.
- the GABA A receptor is composed of a pentamer of transmembrane polypeptide subunits, and 19 different subunits assemble into various GABA A receptor subtypes.
- the GABA A receptor is involved in pathogenesis, diagnosis and treatment of various conditions such as anesthesia, depression, anxiety, epilepsy, memory disorders, and drug dependence, and has accordingly become a pharmacologically and clinically important target for drugs.
- Propofol and its derivatives represent a marked class of GABA A -targeting compounds.
- Propofol can activate many GABA A receptor subtypes, and is a clinically sophisticated venous anesthetic widely used for induction and maintenance of general anesthesia.
- Clinical dosage-related propofol can directly activate the GABA A receptor-chloride channel complex in mammalian neurons, thereby enhancing transportation of Cl ⁇ , reducing excitability of the neural network, and in turn inducing general anesthesia (Manami Hara, et al., (1993) Anesthesiology, 79, 781-788).
- Propofol shows remarkable pharmacokinetic and pharmacodynamic characteristics in that it rapidly takes effect, acts for a short period, and is quickly reversible.
- propofol in the blood rapidly enters hyperperfusion sites such as heart, lung and liver, and its high liposolubility allows propofol to easily travel across the blood-brain barrier into the brain to affect general anesthesia.
- propofol has obvious limitations and disadvantages. It has been reported that approximately 70% of patients on propofol injections feel certain pain or discomfort (Pascale Picard (2000) Anesthesia & Analgesia, 90, 963-969), which is reportedly believed to be injection-induced pain caused by propofol in the aqueous phase of a lipid emulsion (Klement W, et al., 1991, Br J Anaesth 67, 281).
- propofol can lower the systolic pressure, the diastolic pressure, and the mean arterial pressure, and thus may clinically cause hypotension. Furthermore, respiratory depression is also an unneglectable risk upon use of propofol. These adverse effects have considerably impeded application of propofol in certain clinical cases, such as cardiovascular diseases, brain injury, and chronic hypotension.
- Fospropofol is a water-soluble prodrug of propofol, and can be rapidly hydrolyzed by alkaline phosphatase to release propofol, phosphate, and formaldehyde.
- fospropofol relieves pain at sites of intravenous propofol injection, it still poses risks of respiratory depression and adverse haemodynamic effects (Cohen L B (2008) Aliment Pharmacol Ther, 27, 597) because it takes effect in the form of the active compound propofol.
- fospropofol may also cause abnormal sensation and itching.
- An objective of the present invention is to introduce a new group of propofol derivatives that take effect faster, act for a similar period, and have a greater therapeutic index as compared to propofol, and also reduce the likelihood of pain on injection thanks to their increased liposolubility (A W Doenicke, et al., (1996) Anesth Analg, 82, 472-474).
- WO2009140275 describes a propofol analog or a pharmaceutically acceptable salt thereof, useful as an anesthetic, wherein X may be a hydrogen or fluorine atom.
- X may be a hydrogen or fluorine atom.
- EP1206934 describes a phenol derivative or a pharmaceutically acceptable salt or prodrug thereof, useful for local anesthesia, anti-arrhythmia and anti-convulsion, wherein, R 1 , R 3 , R 4 , R 5 and R 6 each are a hydrogen atom, a halogen atom, or C 1-7 alkyl; R 2 is C 1-7 alkyl or hydroxyl; alternatively, R 1 and R 2 may optionally form a 5- or 6-membered ring.
- R 1 , R 3 , R 4 , R 5 and R 6 each are a hydrogen atom, a halogen atom, or C 1-7 alkyl
- R 2 is C 1-7 alkyl or hydroxyl
- R 1 and R 2 may optionally form a 5- or 6-membered ring.
- the general formula of the compound of this invention is shown below:
- WO03026632 describes a phenol derivative or a pharmaceutically acceptable salt thereof, useful for anesthesia and sedation, wherein R 1 and R 2 are each independently selected from C 1-8 alkyl or C 1-8 cycloalkyl; L is selected from a covalent bond or C 1-12 hydrocarbylene; and R 3 is selected from —C( ⁇ O)OR a , wherein R a is selected from C 1-12 hydrocarbyl.
- the general formula of the compound of this invention is shown below:
- WO2008008492 describes a substituted hydrofluoroalkyl phenol compound and a pharmaceutically acceptable salt or prodrug thereof, useful as an anesthetic, wherein R 1 is a substituted or unsubstituted branched C 3-6 alkyl; R 2 is a hydrogen atom, or a substituted or unsubstituted C 1-3 alkyl; R 3 is a C 1-3 fluoroalkyl.
- alkyl refers to a saturated aliphatic group, including linear, branched and cyclic alkyl groups
- a substituted alkyl refers to an alkyl in which one or more hydrogen atoms on a carbon atom have been substituted with substituents, and the substituents include fluorine, chlorine, bromine, iodine, hydroxyl, alkoxy, cyano, amino, mercapto, alkylthio, nitro, and azido.
- substituents include fluorine, chlorine, bromine, iodine, hydroxyl, alkoxy, cyano, amino, mercapto, alkylthio, nitro, and azido.
- WO2006106906 describes preparation of a cyclopropyl phenol derivative represented by the general formula below,
- R 1 , R 2 , R 3 , and R 4 may each independently be hydrogen, F, Cl, Br, I, optionally substituted C 1-6 alkyl, etc.; Z is hydrogen, optionally substituted C 1-6 alkyl, etc.; Y 1 , Y 2 and Y 3 are hydrogen atoms.
- the specific descriptions in WO2006106906 are not considered as part of the present invention.
- the objective of the present invention is to provide a structurally novel GABA A receptor agonist that has improved drug efficacy and safety and can cause less pain on injection, or any of a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a cocrystal or a prodrug thereof, as well as a preparation method thereof, a pharmaceutical composition thereof, and use of the compound of the present invention in the field of the central nervous system, whereby providing more and better choices for medicaments for inducing and maintaining anesthesia in an animal or a human, facilitating sedation and hypnosis, or treating and preventing anxiety, nausea, vomiting, migraine, convulsion, epilepsy, nervous degenerative diseases and central nervous system-associated diseases.
- the present invention relates to a compound of general formula (A),
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, a 3- to 8-membered carbocyclic group, or a 3- to 8-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not all H; Alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 8-membered ring, the 3- to 8-membered ring may have 0 to
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
- Y is preferably H, PEG, COR 13 , CONR 13 R 14 ,
- H more preferably H, PEG, or
- R 13 and R 14 are each independently selected from H, C 1-6 alkyl, a 3- to 8-membered carbocyclic or heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
- R 15 and R 16 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, wherein the alkali metal ion is selected from Na + , K + or Li + , the alkali earth metal ion is selected from Be 2+ , Mg 2+ or Ca 2+ , the alkali earth metal
- a preferred embodiment of the present invention comprises a compound of general formula (A), or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, a 3- to 6-membered carbocyclic group, or a 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 6-membered ring, the 3- to 6-membered ring may have 0 to 2 heteroatoms selected from
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
- Y is preferably H, PEG, COR 13 , CONR 13 R 14 ,
- H more preferably H, PEG, or
- R 13 and R 14 are each independently selected from H or C 1-6 alkyl
- R 15 and R 16 are each independently selected from H or an alkali metal ion, wherein the alkali metal ion is selected from Na + , K + or Li +
- R 17 is the side-chain group of an L-amino acid, wherein the L-amino acid is selected from lysine, arginine, histidine, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid or glutamic acid, and preferably lysine, arginine, or histidine
- X is selected from H, F or carboxyl, preferably H or F, and
- Another preferred embodiment of the present invention comprises a compound of general formula (A), or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
- Y is preferably H, PEG,
- n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
- Another preferred embodiment of the present invention comprises a compound of general formula (A), or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Cl, Br, I, OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered ring, the 3- to 5-membered ring has 0 to 2 heteroatoms selected from N
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
- R 13 and R 14 are each independently selected from H, C 1-6 alkyl, a 3- to 8-membered carbocyclic or heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
- Another preferred embodiment of the present invention comprises a compound of general formula (A), or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, a 3- to 6-membered carbocyclic group, or a 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-7 alkyl, C 1-7 alkoxy, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 6-membered ring, the 3- to 6-membered ring may have 0 to 2 heteroatoms selected from
- R 13 and R 14 are each independently selected from H or C 1-6 alkyl
- R 15 and R 16 are each independently selected from H or an alkali metal ion, wherein the alkali metal ion is selected from Na + , K + or Li +
- R 17 is the side-chain group of an L-amino acid, wherein the L-amino acid is selected from lysine, arginine, histidine, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid or glutamic acid, and preferably lysine, arginine, or histidine
- X is selected from H, F or carboxyl, preferably H or F, and more
- Another preferred embodiment of the present invention comprises a compound of general formula (A), or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from
- Another preferred embodiment of the present invention comprises a compound of general formula (A), or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from
- Another preferred embodiment of the present invention is a compound of general formula (I):
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, preferably H, F, hydroxyl, C 1-5 alkyl, C 1-5 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C 1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3-
- Another preferred embodiment of the present invention comprises a compound of general formula (I) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, preferably H, F, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C 1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membere
- Another preferred embodiment of the present invention comprises a compound of general formula (I) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Cl, Br, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, preferably H, F, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C 1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membere
- Another preferred embodiment of the present invention comprises a compound of general formula (I) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Br, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-5 alkyl, C 1-5 alkoxy, or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C 1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, hydroxyl, C 1-5 alkyl, C 1-5 alkoxy or a 3- to 5-membered carbocyclic group; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and
- Another preferred embodiment of the present invention comprises a compound of general formula (I) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Br, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-5 alkyl, C 1-5 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C 1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C 1-5 alkyl, C 1-5 alkoxy or a 3- to 5-membered carbocyclic group, and R 1 , R 2 and R 3 are not all H; wherein more preferably the alkyl,
- Another preferred embodiment of the present invention comprises a compound of general formula (I) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Br or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C 1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R
- Another preferred embodiment of the present invention comprises a compound of general formula (I) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from Br or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C 1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R
- Another preferred embodiment of the present invention comprises a compound of general formula (I) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein, the compound is selected from a compound of general formula (II):
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C 1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1
- Another preferred embodiment of the present invention comprises a compound of general formula (II) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C 1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, hydroxyl, C 1-4 alkyl, or C 1-4 alkoxy, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may
- Another preferred embodiment of the present invention comprises a compound of general formula (II) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or a 3- to 5-membered carbocyclic group, and more preferably H, C 1-3 alkyl, or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F or hydroxyl, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 substituents selected
- Another preferred embodiment of the present invention comprises a compound of general formula (II) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or a 3- to 5-membered carbocyclic group, and more preferably H, C 1-3 alkyl, or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F or hydroxyl, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 substituents selected
- Another preferred embodiment of the present invention comprises a compound of general formula (II), or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R 1 , R 2 and R 3 are each independently selected from: H, F, Cl, Br, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, cyclopropyl or cyclobutyl, where R 1 , R 2 and R 3 are not all H; preferably H, F, Br, CH 2 F, hydroxyl, methyl, ethyl, methoxy, ethoxy, n-propyl, isopropyl, sec-butyl, cyclopropyl, or cyclobutyl, where R 1 , R 2 and
- Another preferred embodiment of the present invention comprises a compound of general formula (II), or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R 1 , R 2 and R 3 are each independently selected from H, F, Br, CH 2 F, CHFCH 2 F, hydroxyl, methyl, ethyl, methoxy, ethoxy, n-propyl, isopropyl, sec-butyl, cyclopropyl or cyclobutyl, preferably H, F, CH 2 F, hydroxyl, methyl, ethyl or cyclopropyl, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form cyclopropyl; R 4 and R 5 are each independently selected from H, F, hydroxyl, methyl, ethyl, methoxy or ethoxy, preferably H, hydroxyl, methyl or ethyl, and R 4 and R 5 are not both H; and R 6 is selected from H.
- Another preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered ring, the 3- to 5-membered ring has 0 to 2 heteroatoms selected from N,
- Another preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from F, Br, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-5 alkyl, C 1-5 alkoxy, or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-membered carbocyclic group, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered carbocycle, and the carbocycle may optionally be further substituted with 0 to 4 R 8 s; R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-membered carb
- Another preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R is selected from Br or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-membered carbocyclic group, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R 8 s; R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-
- Another preferred embodiment of the present invention is a compound of general formula (I) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein, the compound is selected from a compound of general formula (II):
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered carbocyclic group, preferably a 3-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R 8 s; R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl,
- Another preferred embodiment of the present invention is a compound of general formula (II), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F or hydroxyl, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 substituents selected from F or hydroxyl; R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted
- Another preferred embodiment of the present invention is a compound of general formula (II), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
- R 1 , R 2 and R 3 are each independently selected from H, hydroxyl, C 1-4 alkyl or a 3- to 5-membered carbocyclic group; wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F or hydroxyl, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 substituents selected from F or hydroxyl; R 4 and R 5 are each independently selected from H, hydroxyl, cyano, C 1-4 alkyl or a 3- to 5-membered carbocyclic group; wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 3 hydroxyls, and R 4 and R 5 are not both H; R 6 is selected from H or hydroxyl; and n
- Another preferred embodiment of the present invention is a compound of general formula (I) or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein, the compound is selected from a compound of general formula (II), wherein,
- R 1 , R 2 and R 3 are each independently selected from H, hydroxyl, methyl, ethyl or cyclopropyl, and R 1 , R 2 and R 3 are not all H;
- any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form cyclopropyl
- R 4 and R 5 are each independently selected from H, hydroxyl, cyano, methyl, ethyl or cyclopropyl, and R 4 and R 5 are not both H;
- R 6 is selected from H or hydroxyl
- n is selected from 1 or 2.
- Yet another preferred embodiment of the present invention relates to a compound selected from, but not limited to:
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R 9 , R 10 , R 11 and R 12 are H;
- y is selected from H, PEG,
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
- R 13 and R 14 are each independently selected from H or C 1-6 alkyl;
- R 15 and R 16 are each independently selected from H or an alkali metal ion, wherein the alkali metal ion is selected from Na + , K + or Li + ;
- W 1 , W 2 and W 3 are each independently selected from NR y8 , O or S;
- W 4 is selected from CR y9 R y10 , NR y8 , O, S, or is absent;
- R y1 is each independently selected from H, C 1-6 alkyl, a C
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein Y is selected from C 1-10 alkyl, —(CH 2 CH 2 O) q —H, —(CR ya R yb ) m1 COOR y1 , —(CR ya R yb ) m1 —(W 1 ) p —C( ⁇ O)(W 4 R y3 ) or —(CR ya R yb ) m1 —(W 1 ) p —P( ⁇ O)(W 2 R y4 )(W 3 R y5 ) or
- C 1-6 alkyl further preferably C 1-6 alkyl, —(CH 2 CH 2 O) q —H, —(CR ya R yb ) m1 —(W 1 ) p —C( ⁇ O)(W 4 R y3 ) or —(CR ya R yb ) m1 —(W 1 ) p —P( ⁇ O)(W 2 R y4 )(W 3 R y5 ) or
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, a C 3 carbocyclic group, a C 4 carbocyclic group, a C 5 carbocyclic group, a C 6 carbocyclic group, a C 7 carbocyclic group, a C 8 carbocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 7-membered heterocyclic group, or a 8-membered heterocyclic group; preferably substituted with substituents from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl, a C 3 carbocyclic group, a C 4 carbocyclic group, a C 5 carbocyclic group, or a C 6 carbo
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- W 1 , W 2 and W 3 are each independently selected from NR y8 , O or S, preferably NR y8 or O;
- W 4 is selected from CR y9 R y10 , NR y8 , O, S, or is absent; preferably CR y9 R y10 , NR y8 , O or absent;
- R y8 s are each independently selected from H or C 1-6 alkyl, preferably H or C 1-4 alkyl, and more preferably H, methyl or ethyl;
- R y9 and R y10 are each independently selected from H, C 1-6 alkyl, a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group; preferably H, C 1-6 alkyl, a C 3-6 carbocyclic group or a 4- to 6-membered heterocyclic group; more preferably H, C 1-6 alkyl or a 4- to 6-membered heterocyclic group; even more preferably H or C 1-4 alkyl; and further more preferably H, methyl, isopropyl, sec-butyl, 2-methylpropyl or benzyl; wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C 1-6 alkyl, C 1-6 alkoxy, a C 3 carbocyclic group, a C 4 carbocyclic group, a C
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R y1 is each independently selected from H, C 1-6 alkyl, a C 3 carbocyclic group, a C 4 carbocyclic group, a C 5 carbocyclic group, a C 6 carbocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, or a 6-membered heterocyclic group; preferably H, C 1-6 alkyl, a C 5 carbocyclic group, a C 6 carbocyclic group, a 5-membered heterocyclic group, or a 6-membered heterocyclic group; further preferably H or C 1-6 alkyl; more preferable H or C 1-4 alkyl; and even more preferably H, methyl, ethyl or isopropyl; wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 al
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R y3 is selected from H, amino, C 1-6 alkyl, a C 3 carbocyclic group, a C 4 carbocyclic group, a C 5 carbocyclic group, a C 6 carbocyclic group, a C 7 carbocyclic group, a C 8 carbocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 7-membered heterocyclic group, or a 8-membered heterocyclic group, —(CR ya R yb ) m1 —NR yc R yd or —(CR ya R yb ) m1 —NR yc C( ⁇ O)OR yd ; preferably H, amino, C 1-6 alkyl, a C 3 carbocyclic group, a C 4 carbocyclic group, a C 5 carbocyclic group, a C 6 carbocyclic group, a 4-membere
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R y4 and R y5 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, C 1-6 alkyl, —(CR ya R yb ) m1 -(3- to 8-membered ring), —(CR ya R yb ) m1 —OC( ⁇ O)C 1-6 alkyl, —(CR ya R yb ) m1 —OC( ⁇ O)-(3- to 8-membered ring), —(CR ya R yb ) m1 —C( ⁇ O)OC 1-6 alkyl or —(CR ya R yb ) m1 —OC( ⁇ O)OC 1-6 alkyl; preferably H, an alkali metal ion, an alkali earth metal ion, C 1-6 alkyl, —(CR ya R y
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R y6 and R y7 are each independently selected from H, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl or C 1-6 alkoxy; preferably H, C 1-4 alkyl or C 1-4 alkoxy; and further preferably H or C 1-4 alkyl;
- R y6 and R y7 together with the atoms to which they are attached, may form a 5- to 8-membered ring, preferably a 5- to 6-membered ring, more preferably phenyl; the ring may have 1 to 4 heteroatoms selected from N, O or S; and the ring may optionally be further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, C 1-6 alkyl or C 1-6 alkoxy, preferably substituted with 0 to 4 substituents selected from H, C 1-4 alkyl or C 1-4 alkoxy.
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R y9 and R y10 are each independently selected from H, C 1-6 alkyl, a C 3 carbocyclic group, a C 4 carbocyclic group, a C 5 carbocyclic group, a C 6 carbocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, or a 6-membered heterocyclic group; preferably H, C 1-6 alkyl, a 4-membered heterocyclic group, a 5-membered heterocyclic group, or a 6-membered heterocyclic group; further preferably H or C 1-4 alkyl; and more preferably H, methyl, isopropyl, sec-butyl, 2-methylpropyl or benzyl; wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C 1-6 alky
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein R ya , R yb , R yc and R yd are each independently selected from H or C 1-6 alkyl, preferable H or C 1-4 alkyl, more preferably H, methyl, ethyl, propyl or isopropyl.
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R is selected from F, Cl, Br, I, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered ring, the 3- to 5-membered ring has 0 to 2 heteroatoms selected from N
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group;
- R 13 and R 14 are each independently selected from H or C 1-6 alkyl; and
- R 15 and R 16 are each independently selected from H or an alkali metal ion, wherein the alkali metal ion is selected from Na + , K + or Li + .
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R 9 , R 10 , R 11 and R 12 are H;
- R is selected from Br, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-5 alkyl, C 1-5 alkoxy, or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-membered carbocyclic group, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R 8 s; R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group;
- R 13 and R 14 are each independently selected from H or C 1-6 alkyl;
- R 15 and R 16 are each independently selected from H or an alkali metal ion, wherein the alkali metal ion is selected from Na + , K + or Li + ;
- R y1 is each independently selected from H, C 1-6 alkyl, a C 3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein R 9 , R 10 , R 11 and R 12 are H;
- R is selected from Br, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-membered carbocyclic group, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R 8 s; R 4 and R 5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, or a 3- to 5-
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-6 alkyl, or a C 3-6 carbocyclic group;
- W 1 , W 2 and W 3 are each independently selected from NR y8 , O or S;
- W 4 is selected from CR y9 R y10 , NR y8 , O, S, or is absent;
- R y3 is selected from H, amino, C 1-6 alkyl, a C 3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, —(CR ya R yb ) m1 —NR yc R yd or —(CR ya R yb ) m1 —NR yc C( ⁇ O)OR yd , wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R 9 , R 10 , R 11 and R 12 are H;
- R is selected from Br, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, hydroxyl, methyl, ethyl or cyclopropyl, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form cyclopropyl; R 4 and R 5 are each independently selected from H, hydroxyl, cyano, methyl, ethyl or cyclopropyl, and R 4 and R 5 are not both H; X is H; R 7 is selected from H, methyl or ethyl; Y is selected from C 1-4 alkyl, —(CR ya R yb ) m1 —(W 1 ) p —C( ⁇ O)(W 4 R y3 ) or —(CR ya R yb ) m1 —(W 1 ) p —P( ⁇ O)(W 2 R y4 )(W 3 R
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C 1-4 alkyl, or a C 3-6 carbocyclic group;
- W 1 , W 2 and W 3 are each independently selected from NR y8 , O or S;
- W 4 is selected from CR y9 R y10 , NR y8 , O, S, or is absent;
- R y3 is selected from H, amino, C 1-6 alkyl, a C 3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, —(CR ya R yb ) m1 —NR yc R yd or —(CR ya R yb ) m1 —NR yc C( ⁇ O)OR yd , wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R 9 , R 10 , R 11 and R 12 are H;
- R is selected from Br, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, hydroxyl, methyl, ethyl or cyclopropyl, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form cyclopropyl; R 4 and R 5 are each independently selected from H, hydroxyl, cyano, methyl, ethyl or cyclopropyl, and R 4 and R 5 are not both H; X is H; R 7 is selected from H, methyl or ethyl; Y is selected from C 1-4 alkyl, —(CR ya R yb ) m1 —(W 1 ) p —C( ⁇ O)(W 4 R y3 ) or —(CR ya R yb ) m1 —(W 1 ) p —P( ⁇ O)(W 2 R y4 )(W 2 R
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, C 1-4 alkyl, or a C 5-6 carbocyclic group;
- R y3 is selected from H, amino, C 1-4 alkyl, —(CR ya R yb ) m1 —NR yc R yd , —(CR ya R yb ) m1 —NR yc C( ⁇ O)OR yd , a C 3-6 carbocyclic group or a 3- to 6-membered heterocyclic group; preferably H, amino, C 1-4 alkyl, —(CH 2 ) m1 —NR yc R yd , —(CH 2 ) m1 —NR yc C( ⁇ O)OR yd , a C 5-6 carbocyclic group or a 5- to 6-membered heterocyclic group; further preferably amino, aminomethylene, isopropyl, t
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
- R 9 , R 10 , R 11 and R 12 are H;
- R is selected from Br, —OR 7 or
- R 1 , R 2 and R 3 are each independently selected from H, hydroxyl, methyl, ethyl or cyclopropyl, and R 1 , R 2 and R 3 are not all H; alternatively, any pair of R 1 and R 2 , R 2 and R 3 , or R 1 and R 3 may form cyclopropyl; R 4 and R 5 are each independently selected from H, hydroxyl, cyano, methyl, ethyl or cyclopropyl, and R 4 and R 5 are not both H; X is H; R 7 is selected from H, methyl or ethyl; Y is selected from C 1-4 alkyl, —(CR ya R yb ) m1 —(W 1 ) p —C( ⁇ O)(W 4 R y3 ) or —(CR ya R yb ) m1 —(W 1 ) p —P( ⁇ O)(W 2 R y4 )(W 2 R
- alkyl is optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, C 1-4 alkyl, or a C 5-6 carbocyclic group
- W 1 , W 2 and W 3 are each independently selected from NH or O
- W 4 is independently selected from CHR y10 , O, or is absent
- R y3 is selected from H, amino, C 1-4 alkyl, —(CH 2 ) m1 —NR yc R yd , —(CH 2 ) m1 —NR yc C( ⁇ O)OR yd , a C 5-6 carbocyclic group or a 5- to 6-membered heterocyclic group; preferably amino, aminomethylene, isopropyl, t-butyl, (t-butoxycarbonyl)amino, (t-butoxycarbonyl)aminomethylene, pyrrolylalkyl, phenyl or pyridinyl; wherein the amino group, alky
- Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein:
- Y is selected from methyl, hydroxyethyl, —CH 2 OC( ⁇ O)(R y3 ), —C( ⁇ O)(R y3 ), —CH 2 OC( ⁇ O)(W 4 R y3 ), —C( ⁇ O)(W 4 R y3 ), —CH(CH 3 )OC( ⁇ O)(W 4 R y3 ), —CH 2 OP( ⁇ O)(W 2 R y4 )(W 3 R y5 ), —P( ⁇ O)(W 2 R y4 )(W 3 R y5 ) or
- W 2 and W 3 are each independently selected from NH or O;
- W 4 is selected from CHR y10 or O;
- R y3 is selected from amino, aminomethylene, isopropyl, t-butyl, (t-butoxycarbonyl)amino, (t-butoxycarbonyl)aminomethylene, pyrrolylalkyl, phenyl or pyridinyl, wherein the amino group, pyrrolylalkyl, phenyl and pyridinyl are optionally further substituted with 0 to 4 substituents selected from t-butoxycarbonyl, acetoxy, or benzyloxycarbonyl;
- R y4 and R y5 are each independently selected from H, Na + , K + , ethyl, benzyl, —CH 2 OC( ⁇ O)C(CH 3 ) 3 , —CH(CH 3 )OC( ⁇ O)CH(CH 3 ) 2 , —CH 2
- the prodrug compounds according to the present invention is selected from, but not limited to:
- the present invention also relates to pharmaceutically acceptable salts of the compound of general formula (A) or (I), wherein the salts include, but not limited to, an alkali metal salt, an alkali earth metal salt, an ammonium salt, a tetraalkylammonium salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, trimethylamine salt, N-methylglucosamine salt, hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, fumarate, hemifumarate, maleate, malate, citrate, succinate, benzenesulfonate, or p-toluenesulfonate; preferable an ammonium salt, a potassium salt, a sodium salt, a calcium salt, a magnesium salt, hydrochloride, acetate, trifluoroacetate, fumarate, benzenesulfonate, or p-toluenesulfonate.
- the present invention relates to a method for preparing the compound of general formula (I) according to the present invention, comprising:
- R′ is selected from H, methyl, ethyl, benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, or t-butyl(dimethyl)silyl
- R, R 4 , R 5 and n have the same definitions as those for the compound of general formula (I);
- X is selected from F, Cl, Br or I; or,
- the present invention relates to a method for preparing a prodrug compound of general formula (A) according to the present invention, comprising:
- the present invention relates to a pharmaceutical composition, comprising: a compound of general formula (I) or (A), or any of a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a cocrystal, or a prodrug thereof; and one or more pharmaceutically acceptable vehicles and/or excipients.
- the present invention relates to a usage of a compound of general formula (I) or (A), or any of a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a cocrystal, or a prodrug thereof, for the manufacture of a medicament for (i) inducing and maintaining anesthesia in an animal or a human, (ii) facilitating sedation and hypnosis of an animal or a human, or (iii) treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsion, and epilepsy; preferably for inducing and maintaining anesthesia in an animal or a human.
- All of the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds according to the present invention include their isotopes. All of the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds according to the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, the hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen) and tritium (T, also known as superheavy hydrogen), the oxygen isotopes include 16 O, 17 O and 18 O, the sulfur isotopes include 32 S, 33 S, 34 S and 36 S, the nitrogen isotopes include 14 N and 15 N, the fluorine isotopes include 17 F and 19 F, the chlorine isotopes include 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
- the carbon isotopes include 12 C,
- Alkyl means a linear or branched saturated aliphatic hydrocarbyl having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Non-limiting examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and various branched isomers thereof.
- the alkyl may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ⁇ O, hydroxyl, mercapto, —SR 18a , nitro, cyano, amino, alkylamino, an amide group, alkenyl, alkynyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, a 3- to 8-membered carbocyclic group, a 3- to 8-membered heterocyclic group, (3- to 8-membered carbocyclyl)oxy, (3- to 8-membered heterocyclyl)oxy, carboxyl, or a carboxylic ester group; wherein R 18a is selected from C 1-6 alkyl, a 3- to 8-membered carbocyclic group, or a 3- to 8-membered heterocyclic group.
- substituents selected from F, Cl, Br, I, ⁇ O, hydroxyl, mercapto, —SR 18
- Alkoxy means —O-alkyl. Non-limiting examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy.
- the alkyl may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ⁇ O, hydroxyl, mercapto, —SR 18a , nitro, cyano, amino, alkylamino, an amide group, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, a carbocyclic group, a heterocyclic group, carbocyclyloxy, heterocyclyloxy, carboxyl, or a carboxylic ester group; wherein R 18a is defined as above. This definition applies to the alkoxys used throughout this Description.
- PEG refers to a polymer containing
- n is an integer of 2 to about 1000, preferably 2 to about 500, more preferably 2 to about 250, more preferably 2 to about 125, even more preferably 2 to about 25.
- Amino means —NH 2 .
- Alkylamino means an amino substituted with one or two alkyls.
- Niro means —NO 2 .
- Haldroxyl means —OH.
- Carboxyl means —COOH.
- Carbonyl means —(C ⁇ O)—.
- a “carboxylic ester group” means —COOR 19a , wherein R 19a is C 1-6 alkyl.
- An “amide group” means —CONR 20a R 21a , wherein R 20a and R 21a are each independently selected from H, alkyl or a carbocyclic group, and R 20a and R 21a may optionally be further substituted with 0 to 3 substituents selected from F, Cl, Br, I, hydroxyl, mercapto, —SR 18a , nitro, cyano, amino, alkylamino, an amide group, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, a carbocyclic group, a heterocyclic group, carbocyclyloxy, heterocyclyloxy, carboxyl, or a carboxylic ester group, wherein R 18a is defined as above.
- ⁇ O is a conventional expression used in the art to refer to an oxygen atom linked via a double bond, for example, the double-bonded oxygen atom linked to the carbon atom in carbonyl.
- “Hydroxyalkyl” refers to an alkyl substituted with 1, 2 or 3 hydroxyls, wherein the alkyl is preferably C 1-4 alkyl. Non-limiting examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl and 2,3-dihydroxypropyl.
- Alkenyl means a linear or branched unsaturated aliphatic hydrocarbyl having 1 to 3 carbon-carbon double bonds, and comprising 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms.
- Non-limiting examples thereof include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and hendecen-3-yl.
- the alkenyl may optionally be further substituted with 0 to 4 substituents selected from F, Cl, Br, I, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, mercapto, an amide group, a carbocyclic group, or a heterocyclic group.
- Alkynyl means a linear or branched unsaturated aliphatic hydrocarbyl having 1 to 3 carbon-carbon triple bonds, and comprising 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms.
- Non-limiting examples thereof include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, hendecyn-3-yl or dodecyn-4-yl.
- the alkynyl may optionally be further substituted with 0 to 4 substituents selected from F, Cl, Br, I, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, mercapto, an amide group, a carbocyclic group, or a heterocyclic group.
- a “carbocyclic group” means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, a 4- to 12-membered bicyclic or a 10- to 15-membered tricyclic system.
- the carbocyclic group may have attached bridge rings or spiral rings. Non-limiting examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,
- the carbocyclic group may optionally be further substituted with 0 to 8 substituents selected from F, Cl, Br, I, ⁇ O, hydroxyl, mercapto, —SR 18a , nitro, cyano, amino, alkylamino, an amide group, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, a carbocyclic group, a heterocyclic group, carbocyclyloxy, heterocyclyloxy, carboxyl, or a carboxylic ester group, wherein R 18a is defined as above. This definition applies to the carbocyclic groups used throughout this Description.
- a “heterocyclic group” means a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, a 4- to 12-membered bicyclic or a 10- to 15-membered tricyclic system, and contains 1 to 3 heteroatoms selected from N, O or S.
- a 3- to 8-membered heterocyclic group is preferred.
- the optionally substituted N or S on the ring of a heterocyclic group may be oxidized into various oxidation states.
- the carbocyclic group may be attached via a heteroatom or a carbon atom, and may have attached bridge rings or spiral rings.
- Non-limiting examples thereof include epoxyethyl, azacyclopropyl, oxzcyclobutyl, azacyclobutyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azacycloheptyl, pyridinyl, furyl, thiophenyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, hexahydropyridinyl, morpholinyl, thiomorpholinyl, 1,3-dithia-, dihydrofuryl, dihydropyranyl, dithiacyclopentyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl,
- the heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ⁇ O, hydroxyl, mercapto, —SR 18a , nitro, cyano, amino, alkylamino, an amide group, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, a carbocyclic group, a heterocyclic group, carbocyclyloxy, heterocyclyloxy, carboxyl, or a carboxylic ester group, wherein R 18a is defined as above. This definition applies to the heterocyclic groups used throughout this Description.
- a “pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to a salt obtained by reaction between a free acid form of the compound of the present invention and a nontoxic inorganic or organic base, or by reaction between a free base form of the compound of the present invention and a nontoxic inorganic or organic acid, wherein the bioavailability and characteristics of the free acid or free base form of the compound of the present invention is retained.
- the inorganic base include Al, Ca, Li, Mg, K, Na and Zn.
- Non-limiting examples of the organic base include ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tetramethylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benethamine penicillin, ethylenediamine, glucosamine, N-methylmethylglucosamine, theobromine, triethanolamine, trometamol, purine, piperazine, piperidine, N-ethylpiperidine and polyamine resin.
- Non-limiting examples of the inorganic and organic acids include sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, methanoic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, pyromucic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, dihydroxylnaphthoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxylpropionic acid, oxa
- a “pharmaceutical composition” refers to a mixture formed by one or more compounds according to the present invention or a pharmaceutically acceptable salt or prodrug thereof and additional chemical components, wherein the “additional chemical components” refer to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
- Carrier means a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and characteristics of a given compound.
- Excipient means an inert substance added into a pharmaceutical composition to facilitate administration of a compound.
- Non-limiting examples thereof include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluent, a granulating agent, lubricant, binder and disintegrant.
- a “prodrug” means a compound that can be converted upon in vivo metabolism into the biologically active compound of the present invention.
- a prodrug of the present invention is prepared by modification of the phenol group of the compound of the present invention. Such a modification can be removed in vivo or by conventional operations, so as to afford the parent compound.
- a prodrug of the present invention is administered to a mammalian individual, it is cleaved to expose a free hydroxyl.
- a “cocrystal” refers to a crystal formed by an active pharmaceutical ingredient (API) and a cocrystal former (CCF) combined via hydrogen bonds or other non-covalent bonds, wherein both API and CCF in their pure form are solid at room temperature and these components are present in a fixed stoichiometric ratio therebetween.
- a cocrystal is a multi-component crystal, including both a binary cocrystal formed by two neutral solids and a multiple cocrystal formed by a neutral solid and a salt or solvate.
- Non-limiting examples thereof include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartate, or glutamic acid, pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, methanoic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, pyromucic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydroxyethy
- Animals include mammals, for example a human, companion animals, zoo animals and domestic animals, preferably a human, horse or dog.
- a “stereoisomer” refers to an isomer of a molecule having its atoms in a different spatial arrangement, including cis-trans-isomer, enantiomer, and conformer.
- a heterocyclic group optionally substituted with alkyl means that the alkyl may be present but is not necessarily present, including both the case where the heterocyclic group is substituted with alkyl and the case where the heterocyclic group is not substituted with alkyl.
- ED 50 median effective dose: dose required to cause 50% of mice to lose their righting reflex in a test.
- ED 95 (95% effective dose): dose required to cause 95% of mice to lose their righting reflex in a test.
- LD 50 median lethal dose
- LD 5 (5% lethal dose): dose required to cause 5% of mice to die in a test.
- Anesthesia induction time and anesthesia maintenance time time recording was started from drug administration, and general symptoms and changes in administration sites and respiration of animals were closely observed. If a normal animal was able to immediately turn its body to normal upright position after being pushed over or made lying on its back, such a reflex was determined as the righting reflex. Otherwise, loss of the righting reflex and the time of loss were recorded, and a reflex recovery time was recorded when the animal restored the righting reflex. The period from finishing of drug administration until loss of the righting reflex was recorded as the anesthesia induction time, and the period from loss of the righting reflex until recovery of the righting reflex was recorded as the anesthesia maintenance time.
- TI therapeutic index, i.e. LD 50 /ED 50
- SI safety index, i.e. LD 5 /ED 95 .
- MTD maximum tolerated dose
- the de-protecting agent is selected from Pd/C, palladium hydroxide, Raney Ni, trifluoroacetic acid, hydrochloric acid, tetrabutylammonium fluoride, aluminum trifluoride, aluminum trichloride or boron trifluoride; or conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at ⁇ 4° C.
- a compound of general formula (I) wherein the reducing condition is selected from triethylsilane/trifluoroacetic acid, Pd/C, trimethylsilane chloride/sodium iodide, or carbon disulfide/sodium hydride;
- X is selected from F, Cl, Br or I;
- R, R 4 , R 5 and n have the same definitions as those for the compound of general formula (I); and R′ is defined as above; or,
- organolithium reagent is selected from n-butyllithium, t-butyllithium, phenyllithium; diisopropylaminolithium or lithium hexamethyldisilylamide, and the de-protecting agent is as described above; or allowing a compound of general formula (I-c) to react with a compound of general formula (I-d) for 30 min to 8 h under the action of an organolithium reagent in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at ⁇ 78° C.
- a compound of general formula (I) wherein the reducing condition includes triethylsilane/trifluoroacetic acid, Pd/C, trimethylsilane chloride/sodium iodide, or carbon disulfide/sodium hydride, and the organolithium reagent, the reducing agent, and the de-protecting agent are as described above; or allowing a compound of general formula (I-c) and a compound of general formula (I-d) to undergo a Grignard reaction for 2 to 20 h under stirring in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at ⁇ 4° C.
- the reducing condition includes triethylsilane/trifluoroacetic acid, Pd/C, trimethylsilane chloride/sodium iodide, or carbon disulfide/sodium hydride, and the organolithium reagent,
- the alkylating agent is selected from iodomethane, methyl p-toluenesulfonate, dimethyl sulfate, bromoethane, ethyl p-toluenesulfonate or diethyl sulfate, and the organolithium reagent, the reducing agent, and the de-protecting agent are as described above; wherein R, R 4 , R 5 and n have the same definitions as those for the compound of general formula (I); and R′′ is defined as above.
- the present invention relates to a method for preparing a prodrug compound of general formula (A) according to the present invention, comprising:
- R 18 or R 19 is each independently selected from F, Cl, Br, I, C 1-10 alkyl or C 1-10 alkoxy; V is selected from F, Cl, Br, I; and n, R, R 4 , R 5 and R 6 have the same definitions as those in general formula (I); allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to directly afford a compound of general formula (I-B); or allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-B), and subjecting the intermediate to hydrolysis and then to an exchange reaction with a metal salt to afford a compound of general formula (I-B); or allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to afford
- the metal salt is an organic or inorganic salt of metal, preferably an alkali metal salt or alkali earth metal salt; the alkali includes inorganic or organic alkali, preferably triethylamine, diisopropylethylamine or sodium hydride; the reaction temperature selected is ⁇ 80° C. to 150° C.; and the reaction duration is 5 min to 2 days; or,
- R 20 , R 21 and R 22 are each independently selected from H, F, Cl, Br, I or C 1-10 alkyl; V is selected from F, Cl, Br, I; and n, R, R 4 , R 5 and R 6 have the same definitions as those in general formula (I); allowing a compound of general formula (I) and a compound of general formula (I-C) to undergo nucleophilic substitution to afford a compound of general formula (I-D); and then
- FIG. 3 shows the measurement results for the concentration of free API in aqueous phase.
- NMR nuclear magnetic resonance
- MS mass spectrometry
- silica gel plate for thin-layer chromatography TLC
- HSGF254 Yamamoto Sea
- GF254 Qingdao silica gel plate
- the silica gel plate for TLC had the specification of 0.15 mm to 0.20 mm, while TLC separation and purification used a specification of 0.4 mm to 0.5 mm.
- Known starting materials in connection with the present invention can be synthesized following or using methods known in the art, or can be purchased from companies such as Titansci, Energy Chemical, Demochem (Shanghai), Kelong Chemical (Chengdu), Accela ChemBio, and J&K Scientific.
- a N 2 atmosphere means that the reaction vessel is connected to a N 2 balloon of about 1 L in volume.
- a H 2 atmosphere means that the reaction vessel is connected to a H 2 balloon of about 1 L in volume.
- Hydrogenation reactions generally involve a vacuuming and H 2 -charging operation repeating 3 times.
- solutions refer to aqueous solutions.
- reaction temperatures are room temperature, most suitable room temperature as a reaction temperature is 20° C. to 30° C.
- DMSO dimethyl sulfoxide
- Soluto HS15 polyethylene glycol stearic acid 15;
- RT retention time of a peak.
- Step 2 cyclopropyl-(3-isopropyl-2-tetrahydropyran-2-yloxy-phenyl)methanone (3C)
- Step 5 2-(1-cyclopropylethyl)-6-isopropylphenol (Compound 3)
- dichloromethane (10 mL) was added into reaction flask, diethylzinc (1.21 g, 9.80 mmol) and trifluoroacetic acid (1.12 g, 9.80 mmol) were slowly added dropwise under ice bath, the mixture was stirred for 30 minutes.
- Methylene iodide (2.63 g, 9.80 mmol) was added with ice bath and stirred for 30 min.
- 2-(but-3-en-2-yl)-6-sec-butylphenol (4C) (1.00 g, 4.90 mmol), stirred for 4 h at room temperature.
- Step 2 2-cyclopropyl-6-(1-cyclopropylethyl)phenol (Compound 5)
- Step 2 2-(1-cyclopropylethyl)-6-(1-methylcyclopropyl)phenol (Compound 6)
- reaction mixture was washed with water (2 L ⁇ 3), a solution of sodium hydroxide (2 L ⁇ 4), water (2 L ⁇ 2), brine (2 L ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 2-(2-isopropylphenoxy)tetrahydropyran (7B) (crude product), which was used in the next step without further purification.
- Step 2 cyclobutyl(3-isopropyl-2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)methanone (7C)
- cyclobutyl(3-isopropyl-2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl) methanone (7C) (50.00 g, crude product) was dissolved in a solution of hydrochloric acid in methanol (1M, 120 mL) and stirred for 30 minutes.
- the residue was extracted with ethyl acetate (120 mL ⁇ 2), washed with saturated brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
- cyclobutyl(2-hydroxy-3-isopropylphenyl)methanone (7D) (12.00 g, 54.97 mmol) and tetrahydrofuran (36 mL) were added into reaction flask, added methylmagnesium bromide (46 mL, 3M) with ice bath, stirred at room temperature for 4 h and quenched with a saturated aqueous of ammonium chloride solution (50 mL).
- the reaction mixture was extracted with ethyl acetate (120 mL ⁇ 2), washed with saturated brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
- Step 2 cyclopropyl-(3-methoxy-2-tetrahydropyran-2-yloxy-phenyl)methanone (8C)
- reaction mixture was quenched with a saturated ammonium chloride solution (1000 mL), the organic phase was collected, washed with water (1000 mL ⁇ 2), brine (1000 mL ⁇ 2), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain cyclopropyl-(3-methoxy-2-tetrahydropyran-2-yloxy-phenyl)methanone (8C) as a red liquid (280 g, crude product), which was submitted to the next step without further purification.
- Cyclopropyl-(3-methoxy-2-tetrahydropyran-2-yloxy-phenyl)methanone (8C) (280 g, 1.01 mol) was added into reaction flask, a solution of hydrochloric acid in methanol (1M, 560 mL) was added under ice bath, stirred for 30 minutes. Sodium carbonate was added to adjust pH to about 7. Water was added (200 mL), the aqueous layer was extracted with ethyl acetate (100 mL ⁇ 3), washed with saturated aqueous solution of sodium chloride (200 mL ⁇ 2).
- cyclopropyl-(2-hydroxy-3-methoxy-phenyl)methanone (8D) 190 g, 988.5 mmol
- tetrahydrofuran 1 L
- methylmagnesium bromide 823 mL, 2.47 mol
- the reaction mixture was quenched with a saturated solution of ammonium chloride (300 mL), the organic layer was washed with water (300 mL ⁇ 2), and brine (300 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure.
- N,O-dimethylhydroxylamine hydrochloride (615.86 g, 6.31 mol) and dichloromethane (6 L) were added into reaction flask, followed by the addition of triethylamine (1.34 Kg, 13.20 mol) dropwise at 10° C. under dry ice bath. Upon completion of the addition, the mixture was stirred for 30 minutes. After the addition of cyclopropanecarboxylic acid chloride (9A) (600 g, 5.74 mol) at 0° C., the reaction was stirred for 2 h at room temperature.
- Step 2 cyclopropyl-(3-isopropyl-2-tetrahydropyran-2-yloxy-phenyl)methanone (9C)
- Step 5 2-(1-cyclopropylpropyl)-6-isopropyl-phenol (Compound 9)
- reaction mixture was stirred overnight at room temperature, added with saturated ammonium chloride solution (30 mL) and concentrated under reduced pressure to remove tetrahydrofuran, extracted with ethyl acetate (100 mL ⁇ 3), washed with saturated brine (100 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
- Compound 13 has two chiral centers, so three optical isomers were obtained after separation, which were compound 18, compound 19 and compound 20 respectively.
- Step 1 2-[(1R)-1-cyclopropylethyl]-6-(1-hydroxy-1-methyl-propyl)phenol (24B)
- the aqueous phase was extracted with ethyl acetate (40 mL ⁇ 2).
- the combined organic phases were washed with saturated brine (50 mL ⁇ 1), dried over anhydrous sodium sulfate for 10 minutes, concentrated under reduced pressure.
- Tetrabutylammonium fluoride trihydrate (4 g, 0.013 mol) was added to the combined organic extracts, and stirred at room temperature for 30 minutes, then water (20 mL) was added, stirred for 3 minutes, stood and separated. The aqueous layer was extracted with dichloromethane (20 mL ⁇ 3), The combined organic extracts were washed with saturated brine (30 mL ⁇ 1), dried over anhydrous sodium sulfate for 10 min, concentrated under reduced pressure.
- the combined organic extracts were added with tetrabutylammonium fluoride trihydrate (100 g, 0.28 mol) and stirred at room temperature for 30 minutes, then water (500 mL) was added, stirred for 3 minutes, stood and separated. The aqueous layer was extracted with dichloromethane (100 mL ⁇ 3). The combined organic extracts were washed with saturated brine (200 mL ⁇ 1), dried over anhydrous sodium sulfate for 10 minutes, and concentrated under reduced pressure.
- Peak 1 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.09-7.12 (m, 1H), 7.00-7.02 (m, 1H), 6.89 (t, 1H), 4.88 (s, 1H), 2.87-2.93 (m, 1H), 2.46-2.56 (m, 1H), 1.55-1.69 (m, 2H), 1.29 (d, 3H), 1.24 (d, 3H), 1.02-1.08 (m, 1H), 0.89 (t, 3H), 0.53-0.58 (m, 1H), 0.43-0.49 (m, 1H), 0.16-0.23 (m, 2H).
- Peak 2 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.09-7.12 (m, 1H), 7.00-7.02 (m, 1H), 6.89 (t, 1H), 4.88 (s, 1H), 2.87-2.93 (m, 1H), 2.46-2.56 (m, 1H), 1.55-1.69 (m, 2H), 1.29 (d, 3H), 1.24 (d, 3H), 1.02-1.08 (m, 1H), 0.89 (t, 3H), 0.53-0.58 (m, 1H), 0.43-0.49 (m, 1H), 0.16-0.23 (m, 2H).
- Dibenzyl phosphate (33A) (5.0 g, 0.018 mol) was dissolved into a mixture of dichloromethane (50 mL) and water (50 mL), then, tetrabutylammonium sulphate (1.22 g, 0.0036 mol) and sodium bicarbonate (6.0 g, 0.072 mol) was added under ice-water bath, followed by adding chloromethanesulfonyl chloride (2.97 g, 1.9 mL), and the mixture was stirred overnight at room temperature, stood and separated, and extracted with dichloromethane (50 mL).
- Step 2 [[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methoxy-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate (Compound 35)
- Step 1 [[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methoxy-(isopropoxycarbonyloxymethoxy)phosphoryl]oxymethyl isopropyl carbonate (Compound 36)
- Step 1 ethyl2-[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methoxy-(2-ethoxy-2-oxoethoxy)phosphoryl]oxyacetate (Compound 37)
- Step 1 O1-tert-butyl 02-[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl]pyrrolidine-1,3-dicarboxylate (Compound 39)
- Step 3 2-[[2-[(R)-1-cyclopropylethyl]-6-isopropylphenoxy]methoxy]-4Hbenzo[d][1,3,2]dioxaphosphinine 2-oxide (Compound 40)
- Step 1 O1-tert-butylO2-[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl]pyrrolidine-1,2-dicarboxylate (Compound 42)
- Step 1 ethyl2-[[[2-(1-cyclopropylethyl)-6-isopropyl-phenoxy]-[(2-ethoxy-2-oxo-ethyl)amino]phosphoryl]amino]acetate (Compound 43)
- Step 1 ethyl2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-[(2-ethoxy-2-oxoethyl)amino]phosphoryl]amino]acetate (Compound 44)
- reaction mixture was warmed up to room temperature and stirred for 4 h, then glycine ethyl ester hydrochloride (3.01 g, 21.54 mmol) was added and the mixture was stirred for 15 h. The resulting mixture was filtered and concentrated.
- Step 1 [[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methoxy-potassiooxyphosphoryl]oxypotassium (Compound 45)
- reaction mixture was recovered to room temperature and stirred for 4 h, filtered to remove solid.
- Water (20 mL) was added into the filtrate, and then was stirred at room temperature for 3 h, extracted with dichloromethane (50 mL ⁇ 3), washed with saturated brine (50 mL ⁇ 3).
- the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to obtain [2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]dihydrogen phosphate (46B) as a redbrown thick liquid (6.2 g, crude product), which was submitted to the next step without further purification.
- Step 2 [[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-sodiooxy-phosphoryl]oxysodium (Compound 46)
- Step 1 1-[(1R)-1-cyclopropylethyl]-3-isopropyl-2-methoxy-benzene (Compound 50)
- Step 1 [[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl-sodiooxy-phosphoryl]oxysodium (Compound 52)
- the resulting mixture was concentrated in vacuo, and then the residue was dissolved in water (200 mL), the mixture was adjusted to pH 1 with 10% hydrochloric acid solution, extracted with tert-butylmethylether (200 mL ⁇ 3), washed with saturated brine (100 mL ⁇ 1).
- Step 1 [2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl3-(tertbutoxycarbonylamino)propanoate (Compound 54)
- Step 1 [2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl(2S)-2-(tert-butoxycarbonylamino)propanoate (Compound 56)
- Step 1 [2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl(2R)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate (Compound 57)
- Step 1 [2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl(2S)-2-amino-3-methyl-butanoate trifluoroacetate (Compound 58)
- Step 1 [2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl(2S)-2-(tertbutoxycarbonylamino)-4-methyl-pentanoate (Compound 59)
- Step 1 [2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl(2S)-2-amino-4-methyl-pentanoate trifluoroacetate (Compound 60)
- Step 1 [2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl(2S)-2-(tertbutoxycarbonylamino)-3-phenyl-propanoate (Compound 61)
- Step 1 [2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methyl(2S)-2-amino-3-phenylpropanoate trifluoroacetate (Compound 62)
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Abstract
Description
which is structurally very different from the compounds of the present invention. The specific descriptions in WO03026632 are not considered as part of the present invention.
wherein R1, R2, R3, and R4 may each independently be hydrogen, F, Cl, Br, I, optionally substituted C1-6 alkyl, etc.; Z is hydrogen, optionally substituted C1-6 alkyl, etc.; Y1, Y2 and Y3 are hydrogen atoms. The specific descriptions in WO2006106906 are not considered as part of the present invention.
or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
wherein
R is selected from F, Cl, Br, I, —OR7 or
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-8 alkyl, C1-8 alkoxy, a 3- to 8-membered carbocyclic group, or a 3- to 8-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-8 alkyl, C1-8 alkoxy, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
Alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 8-membered ring, the 3- to 8-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 8-membered ring may optionally be further substituted with 0 to 4 R8s;
R4, R5, R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C1-8 alkyl, C1-8 alkoxy, a 3- to 8-membered carbocyclic group, or a 3- to 8-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-8 alkyl, C1-8 alkoxy, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H; preferably, R9, R10, R11 and R12 are each independently selected from H or F;
Alternatively, any pair of R4 and R5, R9 and R10, or R11 and R12 may form a 3- to 8-membered ring, the 3- to 8-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 8-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H, F, Cl, Br, I, hydroxyl or C1-8 alkoxy, preferably H, F, Cl, hydroxyl or C1-8 alkoxy, more preferably H, hydroxyl or C1-8 alkoxy, and even more preferably H or hydroxyl;
R7 is selected from H, C1-8 alkyl, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-8 alkyl, C1-8 alkoxy, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R8 is selected from F, Cl, Br, I, hydroxyl, carboxyl, amino, a carboxylic ester group, an amide group, C1-8 alkyl, C1-8 alkoxy, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
X is selected from H, F or carboxyl, preferably H or F, and more preferably H;
Y is selected from H, COR13, PEG, COOR13, CONR13R14, COSR13,
C1-20 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1COORy1, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S; Y is preferably H, PEG, COR13, CONR13R14,
and even more preferably H;
R13 and R14 are each independently selected from H, C1-6 alkyl, a 3- to 8-membered carbocyclic or heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R15 and R16 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, wherein the alkali metal ion is selected from Na+, K+ or Li+, the alkali earth metal ion is selected from Be2+, Mg2+ or Ca2+, the amine is selected from trometamol, triethanolamine, ethanolamine, triethylamine or N-methylglucosamine, and the amino acid is selected from arginine or lysine;
alternatively, R15 and R16 may form a 3- to 8-membered ring, the 3- to 8-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 8-membered ring may optionally be further substituted with 0 to 4 R8s;
R17 is the side-chain group of an amino acid, wherein the amino acid is selected from lysine, arginine, histidine, proline, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, aspartate, or glutamic acid;
W1, W2 and W3 are each independently selected from NRy8, O or S;
W4 is selected from CRy9Ry10, NRy8, O, S, or is absent;
Ry1 is each independently selected from H, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry3 is selected from H, amino, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, —(CRyaRyb)m1—NRycRyd or —(CRyaRyb)m1—NRycC(═O)ORyd, wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, —(CH2)m1—OC(═O)—C1-6 alkyl, —(CH2)m1—C(═O)O—C1-6 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-6 alkyl, —(CH2)m1—(C3-8 carbocyclic group) or —(CH2)m1-(4- to 8-membered heterocyclic group), and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, C1-6 alkyl, —(CRyaRyb)m1-(3- to 8-membered ring), —(CRyaRyb)m1—OC(═O)C1-6 alkyl, —(CRyaRyb)m1—OC(═O)-(3- to 8-membered ring), —(CRyaRyb)m1—C(═O)OC1-6 alkyl or —(CRyaRyb)m1—OC(═O)OC1-6 alkyl;
Ry6 and Ry7 are each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl or C1-6 alkoxy;
alternatively, Ry6 and Ry7 may form a 5- to 8-membered ring together with the atoms to which they are attached, the 5- to 8-membered ring may have 0 to 4 heteroatoms selected from N, O or S, and the 5- to 8-membered ring may optionally be further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, C1-6 alkyl or C1-6 alkoxy;
Ry8s are each independently selected from H or C1-6 alkyl;
Ry9 and Ry10 are each independently selected from H, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocycle or a 3- to 8-membered heterocycle;
Rya, Ryb, Ryc and Ryd are each independently selected from H or C1-6 alkyl;
q is selected from 1 to 200;
m1 is selected from 0, 1, 2 or 3;
p is selected from 0, 1 or 2;
m is selected from 1 or 2;
n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-7 alkyl, C1-7 alkoxy, a 3- to 6-membered carbocyclic group, or a 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-7 alkyl, C1-7 alkoxy, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 6-membered ring, the 3- to 6-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 6-membered ring may optionally be further substituted with 0 to 4 R8s;
R4, R5, R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-7 alkyl, C1-7 alkoxy, a 3- to 6-membered carbocyclic group, or a 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-7 alkyl, C1-7 alkoxy, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H; preferably, R9, R10, R11 and R12 are each independently selected from H or F;
alternatively, any pair of R4 and R5, R9 and R10, or R11 and R12 may form a 3- to 6-membered ring, the 3- to 6-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 6-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H, F, Cl, Br, I, hydroxyl or C1-7 alkoxy, preferably H, F, Cl, hydroxyl or C1-7 alkoxy, more preferably H, hydroxyl or C1-7 alkoxy, and even more preferably H or hydroxyl;
R7 is selected from H, C1-7 alkyl, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-7 alkyl, C1-7 alkoxy, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R8 is selected from F, Cl, Br, I, hydroxyl, C1-7 alkyl, carboxyl, amino, a carboxylic ester group, an amide group, C1-7 alkoxy, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Y is selected from H, COR13, PEG, COOR13, CONR13R14, COSR13,
C1-20 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1COORy1, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S; Y is preferably H, PEG, COR13, CONR13R14,
and even more preferably H;
R13 and R14 are each independently selected from H or C1-6 alkyl;
R15 and R16 are each independently selected from H or an alkali metal ion, wherein the alkali metal ion is selected from Na+, K+ or Li+;
R17 is the side-chain group of an L-amino acid, wherein the L-amino acid is selected from lysine, arginine, histidine, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid or glutamic acid, and preferably lysine, arginine, or histidine;
X is selected from H, F or carboxyl, preferably H or F, and more preferably H;
m is selected from 1 or 2; and
n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R4, R5, R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H; preferably, R9, R10, R11 and R12 are each independently selected from H or F;
alternatively, any pair of R4 and R5, R9 and R10, or R11 and R12 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H, hydroxyl or C1-6 alkoxy, and preferably H or hydroxyl;
R7 is selected from H, C1-6 alkyl, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R8 is selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, carboxyl, amino, a carboxylic ester group, an amide group, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
X is selected from H or F, and preferably H;
Y is selected from H, PEG,
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S; Y is preferably H, PEG,
—(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3), or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5), and more preferably H, PEG, or
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R4, R5, R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H; preferably, R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl or C1-6 alkyl; and more preferably, R9, R10, R11 and R12 are each independently selected from H or F;
alternatively, any pair of R4 and R5, R9 and R10, or R11 and R12 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s; preferably, either pair of R9 and R10, or R11 and R12 may form a 3- to 5-membered ring;
R6 is selected from H or hydroxyl;
R7 is selected from H, C1-6 alkyl, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R8 is selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, carboxyl, amino, a carboxylic ester group, an amide group, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
X is selected from H or F;
Y is selected from H; and
n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered ring, the 3- to 5-membered ring has 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring is optionally further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H, hydroxyl or C1-6 alkoxy, and preferably H or hydroxyl;
R7 is selected from H, C1-4 alkyl, or a 3- to 5-membered carbocyclic group, wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl or C1-6 alkoxy;
X is selected from H, F or carboxyl, and preferably H;
Y is selected from H, COR13, PEG, COOR13, CONR13R14, COSR13,
C1-20 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1COORy1, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R13 and R14 are each independently selected from H, C1-6 alkyl, a 3- to 8-membered carbocyclic or heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R15 and R16 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, wherein the alkali metal ion is selected from Na+, K+ or Li+, the alkali earth metal ion is selected from Be2+, Mg2+ or Ca2+, the amine is selected from trometamol, triethanolamine, ethanolamine, triethylamine or N-methylglucosamine, and the amino acid is selected from arginine or lysine;
alternatively, R15 and R16 may form a 3- to 8-membered ring, the 3- to 8-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 8-membered ring may optionally be further substituted with 0 to 4 R8s;
R17 is the side-chain group of an amino acid, wherein the amino acid is selected from lysine, arginine, histidine, proline, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, aspartate, or glutamic acid;
W1, W2 and W3 are each independently selected from NRy8, O or S;
W4 is selected from CRy9Ry10, NRy8, O, S, or is absent;
Ry1 is each independently selected from H, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry3 is selected from H, amino, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, —(CRyaRyb)m1—NRycRyd or —(CRyaRyb)m1—NRycC(═O)ORyd, wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, —(CH2)m1—OC(═O)—C1-6 alkyl, —(CH2)m1—C(═O)O—C1-6 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-6 alkyl, —(CH2)m1—(C3-8 carbocyclic group) or —(CH2)m1-(4- to 8-membered heterocyclic group), and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, C1-6 alkyl, —(CRyaRyb)m1-(3- to 8-membered ring), —(CRyaRyb)m1—OC(═O)C1-6 alkyl, —(CRyaRyb)m1—OC(═O)-(3- to 8-membered ring), —(CRyaRyb)m1—C(═O)OC1-6 alkyl or —(CRyaRyb)m1—OC(═O)OC1-6 alkyl;
Ry6 and Ry7 are each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl or C1-6 alkoxy;
alternatively, Ry6 and Ry7 may form a 5- to 8-membered ring together with the atoms to which they are attached, the 5- to 8-membered ring may have 0 to 4 heteroatoms selected from N, O or S, and the 5- to 8-membered ring may optionally be further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, C1-6 alkyl or C1-6 alkoxy;
Ry8s are each independently selected from H or C1-6 alkyl;
Ry9 and Ry10 are each independently selected from H, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocycle or a 3- to 8-membered heterocycle;
Rya, Ryb, Ryc and Ryd are each independently selected from H or C1-6 alkyl;
n is selected from 1, 2 or 3;
m is selected from 1 or 2;
q is selected from 1 to 200;
m1 is selected from 0, 1, 2 or 3; and
p is selected from 0, 1 or 2.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-7 alkyl, C1-7 alkoxy, a 3- to 6-membered carbocyclic group, or a 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-7 alkyl, C1-7 alkoxy, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 6-membered ring, the 3- to 6-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 6-membered ring may optionally be further substituted with 0 to 4 R8s;
R4, R5, R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-7 alkyl, C1-7 alkoxy, a 3- to 6-membered carbocyclic group, or a 3- to 6-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-7 alkyl, C1-7 alkoxy, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H; preferably, R9, R10, R11 and R12 are each independently selected from H or F;
alternatively, any pair of R4 and R5, R9 and R10, or R11 and R12 may form a 3- to 6-membered ring, the 3- to 6-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 6-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H, F, Cl, Br, I, hydroxyl or C1-7 alkoxy, preferably H, F, Cl, hydroxyl or C1-7 alkoxy, more preferably H, hydroxyl or C1-7 alkoxy, and even more preferably H or hydroxyl;
R7 is selected from H, C1-7 alkyl, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-7 alkyl, C1-7 alkoxy, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R8 is selected from F, Cl, Br, I, hydroxyl, C1-7 alkyl, carboxyl, amino, a carboxylic ester group, an amide group, C1-7 alkoxy, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Y is selected from H, PEG, COR13, CONR13R14,
and more preferably H;
R13 and R14 are each independently selected from H or C1-6 alkyl;
R15 and R16 are each independently selected from H or an alkali metal ion, wherein the alkali metal ion is selected from Na+, K+ or Li+;
R17 is the side-chain group of an L-amino acid, wherein the L-amino acid is selected from lysine, arginine, histidine, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid or glutamic acid, and preferably lysine, arginine, or histidine;
X is selected from H, F or carboxyl, preferably H or F, and more preferably H;
m is selected from 1 or 2; and
n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R4, R5, R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H; preferably, R9, R10, R11 and R12 are each independently selected from H or F;
alternatively, any pair of R4 and R5, R9 and R10, or R11 and R12 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H, hydroxyl or C1-6 alkoxy, and more preferably H or hydroxyl;
R7 is selected from H, C1-6 alkyl, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R8 is selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, carboxyl, amino, a carboxylic ester group, an amide group, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
X is selected from H or F, and preferably H;
Y is selected from H; and
n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R4, R5, R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H; preferably, R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl or C1-6 alkyl; and more preferably, R9, R10, R11 and R12 are each independently selected from H or F;
alternatively, any pair of R4 and R5, R9 and R10, or R11 and R12 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s; preferably, either pair of R9 and R10, or R11 and R12 may form a 3- to 5-membered ring;
R6 is selected from H or hydroxyl;
R7 is selected from H, C1-6 alkyl, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R8 is selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, carboxyl, amino, a carboxylic ester group, an amide group, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
X is selected from H or F;
Y is selected from H; and
n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
or any of a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof;
wherein,
R is selected from F, Cl, Br, I, —OR7 or
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, preferably H, F, hydroxyl, C1-5 alkyl, C1-5 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, preferably H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, more preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and even more preferably H, F or C1-3 alkyl; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H, hydroxyl or C1-6 alkoxy, preferably H or hydroxyl, and more preferably H;
R7 is selected from H, C1-6 alkyl, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R8 is selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, carboxyl, amino, a carboxylic ester group, an amide group, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
and
n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, preferably H, F, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C1-3 alkyl, C1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, C1-5 alkyl, C1-5 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, preferably H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, more preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and even more preferably H, F or C1-3 alkyl; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, hydroxyl, C1-5 alkyl, C1-5 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl, and preferably H;
R7 is selected from H, C1-5 alkyl, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-5 alkyl, C1-5 alkoxy, or a 3- to 5-membered carbocyclic group;
R8 is selected from F, Cl, Br, hydroxyl, C1-5 alkyl, C1-5 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
and
n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, preferably H, F, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C1-3 alkyl, C1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, preferably H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, more preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and even more preferably H, F or C1-3 alkyl; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl, and preferably H;
R7 is selected from C1-4 alkyl or a 3- to 5-membered carbocyclic group, wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
and
n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-5 alkyl, C1-5 alkoxy, or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C1-3 alkyl, C1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, hydroxyl, C1-5 alkyl, C1-5 alkoxy or a 3- to 5-membered carbocyclic group;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and more preferably H, F or C1-3 alkyl; wherein the alkyl or alkoxy is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from C1-4 alkyl or a 3- to 4-membered carbocyclic group, wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 5 substituents selected from F, hydroxyl or C1-3 alkyl;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group;
and
n is selected from 1, 2 or 3; preferably 1 or 2, and more preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-5 alkyl, C1-5 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C1-3 alkyl, C1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-5 alkyl, C1-5 alkoxy or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H; wherein more preferably the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and more preferably H, F or C1-3 alkyl; wherein the alkyl or alkoxy is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from C1-4 alkyl or a 3- to 4-membered carbocyclic group, wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, hydroxyl or C1-3 alkyl;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy;
and
n is selected from 1 or 2, and preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C1-3 alkyl, C1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and more preferably H, F or C1-3 alkyl; wherein the alkyl or alkoxy is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl, and preferably H;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and preferably F, hydroxyl or C1-3 alkyl;
and
n is selected from 1 or 2, and preferably 1.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C1-3 alkyl, C1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and more preferably H, F or C1-3 alkyl; wherein the alkyl or alkoxy is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl, and preferably H;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and preferably F, hydroxyl or C1-3 alkyl;
and
n is selected from 1.
wherein,
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, preferably H, F, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, more preferably H, F, hydroxyl, C1-3 alkyl, C1-3 alkoxy or a 3- to 5-membered carbocyclic group, and even more preferably H, C1-3 alkyl or a 3- to 4-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and more preferably H, F or C1-3 alkyl; wherein the alkyl or alkoxy is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl, and preferably H;
and
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and preferably F, hydroxyl or C1-3 alkyl.
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and more preferably H, F or C1-3 alkyl; wherein the alkyl or alkoxy is optionally further substituted with 0 to 3 substituents selected from F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl, and preferably H;
and
R8 is selected from F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and preferably F, hydroxyl or C1-3 alkyl.
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 substituents selected from F or hydroxyl;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and more preferably H, F or C1-3 alkyl; wherein the alkyl or alkoxy is optionally further substituted with 0 to 3 substituents selected from F or hydroxyl, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group;
and
R6 is selected from H or hydroxyl, and preferably H.
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 substituents selected from F or hydroxyl, more preferably substituted with 0 to 2 substituents selected from F or hydroxyl;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, preferably H, F, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and more preferably H, F or C1-3 alkyl; wherein the alkyl or alkoxy is optionally further substituted with 0 to 3 substituents selected from F or hydroxyl, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, preferably a 3- to 4-membered carbocyclic group;
and
R6 is selected from H.
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form cyclopropyl;
R4 and R5 are each independently selected from: H, F, Cl, Br, CH2F, CHF2, CF3, CH2CH2F, CHFCH3, CHFCH2F, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy or t-butoxy; preferably H, F, Br, CF3, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, hydroxymethyl, hydroxyethyl, methoxy, or ethoxy; more preferably H, F, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, or ethoxy; even more preferably H, F, hydroxyl, methyl, ethyl, n-propyl, methoxy, or ethoxy; and R4 and R5 are not both H;
alternatively, R4 and R5 may form cyclopropyl;
and
R6 is selected from H.
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form cyclopropyl;
R4 and R5 are each independently selected from H, F, hydroxyl, methyl, ethyl, methoxy or ethoxy, preferably H, hydroxyl, methyl or ethyl, and R4 and R5 are not both H;
and
R6 is selected from H.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered ring, the 3- to 5-membered ring has 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring is optionally further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group; wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from H, C1-4 alkyl, or a 3- to 5-membered carbocyclic group, wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
and
n is selected from 1, 2 or 3.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-5 alkyl, C1-5 alkoxy, or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocycle, and the carbocycle may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from hydroxyl, C1-4 alkyl, or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from C1-4 alkyl or a 3- to 4-membered carbocyclic group, wherein the alkyl or carbocyclic group may optionally be further substituted with 0 to 3 substituents selected from F, hydroxyl, or C1-3 alkyl;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl, or C1-4 alkoxy;
and
n is selected from 1 or 2.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from hydroxyl, C1-4 alkyl, or C1-4 alkoxy, and R4 and R5 are not both H; alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from C1-4 alkyl or a 3- to 4-membered carbocyclic group, wherein the alkyl or carbocyclic group may optionally be further substituted with 0 to 3 substituents selected from F, hydroxyl, or C1-3 alkyl;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl, or C1-4 alkoxy;
and
n is selected from 1 or 2.
wherein,
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, preferably a 3-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from hydroxyl, C1-4 alkyl or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy, and preferably F or hydroxyl;
and
n is selected from 1 or 2.
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 substituents selected from F or hydroxyl;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group; wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 hydroxyls, and R4 and R5 are not both H;
R6 is selected from H or hydroxyl;
and
n is selected from 1 or 2.
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 substituents selected from F or hydroxyl;
R4 and R5 are each independently selected from H, hydroxyl, cyano, C1-4 alkyl or a 3- to 5-membered carbocyclic group; wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 3 hydroxyls, and R4 and R5 are not both H;
R6 is selected from H or hydroxyl;
and
n is selected from 1 or 2.
C1-20 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1COORy1, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R13 and R14 are each independently selected from H or C1-6 alkyl;
R15 and R16 are each independently selected from H or an alkali metal ion, wherein the alkali metal ion is selected from Na+, K+ or Li+;
W1, W2 and W3 are each independently selected from NRy8, O or S;
W4 is selected from CRy9Ry10, NRy8, O, S, or is absent;
Ry1 is each independently selected from H, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry3 is selected from H, amino, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, —(CRyaRyb)m1—NRycRyd or —(CRyaRyb)m1—NRycC(═O)ORyd, wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, —(CH2)m1—OC(═O)—C1-6 alkyl, —(CH2)m1—C(═O)O—C1-6 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-6 alkyl, —(CH2)m1—(C3-8 carbocyclic group) or —(CH2)m1-(4- to 8-membered heterocyclic group), and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, C1-6 alkyl, —(CRyaRyb)m1-(3- to 8-membered ring), —(CRyaRyb)m1—OC(═O)C1-6 alkyl, —(CRyaRyb)m1—OC(═O)-(3- to 8-membered ring), —(CRyaRyb)m1—C(═O)OC1-6 alkyl or —(CRyaRyb)m1—OC(═O)OC1-6 alkyl;
Ry6 and Ry7 are each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl or C1-6 alkoxy;
alternatively, Ry6 and Ry7 may form a 5- to 8-membered ring together with the atoms to which they are attached, the 5- to 8-membered ring may have 0 to 4 heteroatoms selected from N, O or S, and the 5- to 8-membered ring may optionally be further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, C1-6 alkyl or C1-6 alkoxy;
Ry8s are each independently selected from H or C1-6 alkyl;
Ry9 and Ry10 are each independently selected from H, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocycle or a 3- to 8-membered heterocycle;
Rya, Ryb, Ryc and Ryd are each independently selected from H or C1-6 alkyl;
q is selected from 1 to 200;
m1 is selected from 0, 1, 2 or 3; and
p is selected from 0, 1 or 2.
Another preferred embodiment of the present invention is a compound of general formula (A), or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof; wherein
Y is selected from C1-10 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1COORy1, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
preferably C1-10 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
further preferably C1-6 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
more preferably C1-4 alkyl, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
even more preferably methyl, hydroxyethyl, —CH2OC(═O)(Ry3), —C(═O)(Ry3), —CH2OC(═O)(W4Ry3), —C(═O)(W4Ry3), —CH(CH3)OC(═O)(W4Ry3), —CH2OP(═O)(W2Ry4)(W3Ry5), —P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3 carbocyclic group, a C4 carbocyclic group, a C5 carbocyclic group, a C6 carbocyclic group, a C7 carbocyclic group, a C8 carbocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 7-membered heterocyclic group, or a 8-membered heterocyclic group; preferably substituted with substituents from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, a C3 carbocyclic group, a C4 carbocyclic group, a C5 carbocyclic group, or a C6 carbocyclic group; further preferably substituted with substituents from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-4 alkyl, a C3 carbocyclic group, a C4 carbocyclic group, a C5 carbocyclic group, or a C6 carbocyclic group; more preferably substituted with substituents from H, hydroxyl, amino, C1-4 alkyl, a C5 carbocyclic group, or a C6 carbocyclic group; even more preferably substituted with substituents from H, methyl, ethyl, propyl, isopropyl or phenyl; and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
q is selected from 1 to 100, preferably from 1 to 10, and more preferably 1, 2, 3, 4 or 5;
m1 is selected from 0, 1, 2 or 3, preferably 0, 1 or 2; and
p is selected from 0, 1 or 2, preferably 0 or 1.
wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a C3 carbocyclic group, a C4 carbocyclic group, a C5 carbocyclic group, a C6 carbocyclic group, a C7 carbocyclic group, a C8 carbocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 7-membered heterocyclic group, or a 8-membered heterocyclic group; preferably substituted with substituents from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a C3 carbocyclic group, a C4 carbocyclic group, a C5 carbocyclic group, a C6 carbocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, or a 6-membered heterocyclic group; further preferably substituted with substituents from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-4 alkyl, or a 5- to 6-membered carbocyclic group; more preferably substituted with substituents from H, C1-4 alkyl, or a 5- to 6-membered carbocyclic group; and even more preferably substituted with substituents from H, methyl, ethyl, propyl, isopropyl or phenyl.
wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3 carbocyclic group, a C4 carbocyclic group, a C5 carbocyclic group, a C6 carbocyclic group, a C7 carbocyclic group, a C8 carbocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 7-membered heterocyclic group, or a 8-membered heterocyclic group; preferably substituted with substituents from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C5 carbocyclic group, a C6 carbocyclic group, a 5-membered heterocyclic group, or a 6-membered heterocyclic group; further preferably substituted with substituents from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-4 alkyl, or C1-4 alkoxy; more preferably substituted with substituents from H, methyl, ethyl or isopropyl; and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S.
wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, —(CH2)m1—OC(═O)—C1-6 alkyl, —(CH2)m1—C(═O)O—C1-6 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-6 alkyl, —(CH2)m1—(C3-6 carbocyclic group) or —(CH2)m1-(4- to 6-membered heterocyclic group); preferably substituted with substituents from H, —(CH2)m1—OC(═O)—C1-4 alkyl, —(CH2)m1—C(═O)O—C1-4 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-4 alkyl, —(CH2)m1—(C3-6 carbocyclic group) or —(CH2)m1-(4- to 6-membered heterocyclic group); further preferably substituted with 0-4 substituents selected from H, —OC(═O)—C1-4 alkyl, —C(═O)O—C1-4 alkyl, or —C(═O)CH2—(C5-6 carbocyclic group); more preferably substituted with 0-4 substituents selected from t-butoxycarbonyl, acetoxy or benzyloxycarbonyl; and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S.
wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocycle or a 3- to 8-membered heterocycle; preferably substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle; further preferably substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-4 alkyl, or a 5- to 6-membered carbocycle; and more preferably substituted with 0 to 4 substituents selected from H, C1-4 alkyl, or a 5- to 6-membered carbocycle.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered ring, the 3- to 5-membered ring has 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring is optionally further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from H, C1-4 alkyl, or a 3- to 5-membered carbocyclic group, wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R9, R10, R11 and R12 are H;
X is selected from H, F or carboxyl;
Y is selected from H, PEG,
C1-20 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1COORy1, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group;
R13 and R14 are each independently selected from H or C1-6 alkyl;
and
R15 and R16 are each independently selected from H or an alkali metal ion, wherein the alkali metal ion is selected from Na+, K+ or Li+.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-5 alkyl, C1-5 alkoxy, or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from hydroxyl, C1-4 alkyl, or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from H or C1-4 alkyl;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl, or C1-4 alkoxy;
X is H;
Y is selected from H, PEG,
C1-20 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1COORy1, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group;
R13 and R14 are each independently selected from H or C1-6 alkyl;
R15 and R16 are each independently selected from H or an alkali metal ion, wherein the alkali metal ion is selected from Na+, K+ or Li+;
Ry1 is each independently selected from H, C1-6 alkyl, a C3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry3 is selected from H, amino, C1-6 alkyl, a C3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, —(CRyaRyb)m1—NRycRyd or —(CRyaRyb)m1—NRycC(═O)ORyd, wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, —(CH2)m1—OC(═O)—C1-6 alkyl, —(CH2)m1—C(═O)O—C1-6 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-6 alkyl, —(CH2)m1—(C3-6 carbocyclic group) or —(CH2)m1—(4- to 6-membered heterocyclic group), and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, C1-6 alkyl, —(CRyaRyb)m1-(3- to 6-membered ring), —(CRyaRyb)m1—OC(═O)C1-6 alkyl, —(CRyaRyb)m1—OC(═O)-(3- to 6-membered ring), —(CRyaRyb)m1—C(═O)OC1-6 alkyl or —(CRyaRyb)m1—OC(═O)OC1-6 alkyl;
Ry9 and Ry10 are each independently selected from H, C1-6 alkyl, a C3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocycle or a 3- to 8-membered heterocycle.
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C1-4 alkyl, C1-4 alkoxy, or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy, or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from hydroxyl, C1-4 alkyl, or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from H or C1-4 alkyl;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl, or C1-4 alkoxy;
X is H;
Y is selected from C1-10 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, or a C3-6 carbocyclic group;
W1, W2 and W3 are each independently selected from NRy8, O or S;
W4 is selected from CRy9Ry10, NRy8, O, S, or is absent;
Ry3 is selected from H, amino, C1-6 alkyl, a C3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, —(CRyaRyb)m1—NRycRyd or —(CRyaRyb)m1—NRycC(═O)ORyd, wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, —(CH2)m1—OC(═O)—C1-6 alkyl, —(CH2)m1—C(═O)O—C1-6 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-6 alkyl, —(CH2)m1—(C3-6 carbocyclic group) or —(CH2)m1—(4- to 6-membered heterocyclic group), and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, C1-6 alkyl, —(CRyaRyb)m1-(3- to 6-membered ring), —(CRyaRyb)m1—OC(═O)C1-6 alkyl, —(CRyaRyb)m1—OC(═O)-(3- to 6-membered ring), —(CRyaRyb)m1—C(═O)OC1-6 alkyl or —(CRyaRyb)m1—OC(═O)OC1-6 alkyl;
Ry6 and Ry7 are each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl or C1-6 alkoxy;
alternatively, Ry6 and Ry7 may form a 5- to 8-membered ring together with the atoms to which they are attached, the 5- to 8-membered ring may have 0 to 4 heteroatoms selected from N, O or S, and the 5- to 8-membered ring may optionally be further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, C1-6 alkyl or C1-6 alkoxy;
Ry8s are each independently selected from H or C1-6 alkyl;
Ry9 and Ry10 are each independently selected from H, C1-6 alkyl, a C3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocycle or a 3- to 8-membered heterocycle;
Rya, Ryb, Ryc and Ryd are each independently selected from H or C1-6 alkyl;
n is selected from 1 to 200;
m1 is selected from 0, 1, 2 or 3; and
p is selected from 0, 1 or 2.
R1, R2 and R3 are each independently selected from H, hydroxyl, methyl, ethyl or cyclopropyl, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form cyclopropyl;
R4 and R5 are each independently selected from H, hydroxyl, cyano, methyl, ethyl or cyclopropyl, and R4 and R5 are not both H;
X is H;
R7 is selected from H, methyl or ethyl;
Y is selected from C1-4 alkyl, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-4 alkyl, or a C3-6 carbocyclic group;
W1, W2 and W3 are each independently selected from NRy8, O or S;
W4 is selected from CRy9Ry10, NRy8, O, S, or is absent;
Ry3 is selected from H, amino, C1-6 alkyl, a C3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, —(CRyaRyb)m1—NRycRyd or —(CRyaRyb)m1—NRycC(═O)ORyd, wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from —(CH2)m1—OC(═O)—C1-4 alkyl, —(CH2)m1—C(═O)O—C1-4 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-4 alkyl, —(CH2)m1—(C3-6 carbocyclic group) or —(CH2)m1-(4- to 6-membered heterocyclic group), and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, C1-4 alkyl, —(CRyaRyb)m1-(3- to 6-membered ring), —(CRyaRyb)m1—OC(═O)C1-4 alkyl, —(CRyaRyb)m1—OC(═O)-(3- to 6-membered ring), —(CRyaRyb)m1—C(═O)OC1-4 alkyl or —(CRyaRyb)m1—OC(═O)OC1-4 alkyl;
Ry6 and Ry7 are each independently selected from H, C1-4 alkyl or C1-4 alkoxy;
alternatively, Ry6 and Ry7 may form a 5- to 6-membered ring together with the atoms to which they are attached, and the 5- to 6-membered ring may have 0 to 4 heteroatoms selected from N, O or S;
Ry8s are each independently selected from H or C1-4 alkyl;
Ry9 and Ry10 are each independently selected from H, C1-6 alkyl or a 4- to 6-membered heterocyclic group, wherein the alkyl and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle;
Rya, Ryb, Ryc and Ryd are each independently selected from H or C1-4 alkyl;
q is selected from 1 to 10;
m1 is selected from 0, 1, 2 or 3; and
p is selected from 0, 1 or 2.
R1, R2 and R3 are each independently selected from H, hydroxyl, methyl, ethyl or cyclopropyl, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form cyclopropyl;
R4 and R5 are each independently selected from H, hydroxyl, cyano, methyl, ethyl or cyclopropyl, and R4 and R5 are not both H;
X is H;
R7 is selected from H, methyl or ethyl;
Y is selected from C1-4 alkyl, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W2Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, C1-4 alkyl, or a C5-6 carbocyclic group;
Ry3 is selected from H, amino, C1-4 alkyl, —(CRyaRyb)m1—NRycRyd, —(CRyaRyb)m1—NRycC(═O)ORyd, a C3-6 carbocyclic group or a 3- to 6-membered heterocyclic group; preferably H, amino, C1-4 alkyl, —(CH2)m1—NRycRyd, —(CH2)m1—NRycC(═O)ORyd, a C5-6 carbocyclic group or a 5- to 6-membered heterocyclic group; further preferably amino, aminomethylene, isopropyl, t-butyl, (t-butoxycarbonyl)amino, (t-butoxycarbonyl)aminomethylene, pyrrolylalkyl, phenyl or pyridinyl;
wherein the amino group, alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 4 substituents selected from H, —OC(═O)—C1-4 alkyl, —C(═O)O—C1-4 alkyl or —C(═O)OCH2—(C5-6 carbocyclic group), preferably substituted with 0 to 4 substituents selected from t-butoxycarbonyl, acetoxy or benzyloxycarbonyl; and the heterocyclic group has at least 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, C1-4 alkyl, —(CRyaRyb)m1-(5- to 6-membered ring), —(CRyaRyb)m1—OC(═O)C1-4 alkyl, —(CRyaRyb)m1—C(═O)OC1-4 alkyl or —(CRyaRyb)m1—OC(═O)OC1-4 alkyl; preferably H, an alkali metal ion, C1-4 alkyl, —(CH2)m1-(5- to 6-membered ring), —(CH2)m1—OC(═O)C1-4 alkyl, —(CH2)m1—C(═O)OC1-4 alkyl or —(CH2)m1—OC(═O)OC1-4 alkyl; and more preferably H, Na+, K+, ethyl, benzyl, —CH2OC(═O)C(CH3)3, —CH(CH3)OC(═O)CH(CH3)2, —CH2OC(═O)CH2CH3, —CH2C(═O)OCH2CH3 or —CH2OC(═O)OCH(CH3)2;
Ry6 and Ry7 are each independently selected from H or C1-4 alkyl;
alternatively, Ry6 and Ry7 may form a 5- to 6-membered ring together with the atoms to which they are attached, and the 5- to 6-membered ring may have 0 to 4 heteroatoms selected from N, O or S;
Ry8 is selected from H or C1-4 alkyl;
Ry9 is selected from H or C1-4 alkyl;
Ry10 is selected from H or C1-4 alkyl; wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-4 alkyl, or a 5- to 6-membered carbocycle;
q is selected from 1 to 10;
m1 is selected from 0, 1, 2 or 3; and
p is selected from 0, 1 or 2.
R1, R2 and R3 are each independently selected from H, hydroxyl, methyl, ethyl or cyclopropyl, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form cyclopropyl;
R4 and R5 are each independently selected from H, hydroxyl, cyano, methyl, ethyl or cyclopropyl, and R4 and R5 are not both H;
X is H;
R7 is selected from H, methyl or ethyl;
Y is selected from C1-4 alkyl, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W2Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, C1-4 alkyl, or a C5-6 carbocyclic group;
W1, W2 and W3 are each independently selected from NH or O;
W4 is independently selected from CHRy10, O, or is absent;
Ry3 is selected from H, amino, C1-4 alkyl, —(CH2)m1—NRycRyd, —(CH2)m1—NRycC(═O)ORyd, a C5-6 carbocyclic group or a 5- to 6-membered heterocyclic group; preferably amino, aminomethylene, isopropyl, t-butyl, (t-butoxycarbonyl)amino, (t-butoxycarbonyl)aminomethylene, pyrrolylalkyl, phenyl or pyridinyl;
wherein the amino group, alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 4 substituents selected from H, —OC(═O)—C1-4 alkyl, —C(═O)O—C1-4 alkyl or —C(═O)OCH2—(C5-6 carbocyclic group), preferably substituted with 0 to 4 substituents selected from t-butoxycarbonyl, acetoxy or benzyloxycarbonyl; and the heterocyclic group has at least 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, C1-4 alkyl, —(CH2)m1-(5- to 6-membered ring), —(CH2)m1—OC(═O)C1-4 alkyl, —(CH2)m1—C(═O)OC1-4 alkyl or —(CH2)m1—OC(═O)OC1-4 alkyl; and preferably H, Na+, K+, ethyl, benzyl, —CH2OC(═O)C(CH3)3, —CH(CH3)OC(═O)CH(CH3)2, —CH2OC(═O)CH2CH3, —CH2C(═O)OCH2CH3 or —CH2OC(═O)OCH(CH3)2;
Ry6 and Ry7 are each independently selected from H or C1-4 alkyl;
alternatively, Ry6 and Ry7, together with the atoms to which they are attached, may form a 5- to 6-membered ring, preferably phenyl, and the 5- to 6-membered ring may have 0 to 4 heteroatoms selected from N, O or S;
Ry8 is selected from H or C1-4 alkyl;
Ry9 is selected from H or C1-4 alkyl;
Ry10 is selected from H or C1-4 alkyl, preferably H, methyl, isopropyl, sec-butyl, 2-methylpropyl or benzyl; wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, C1-4 alkyl, or a 5- to 6-membered carbocycle;
Rya, Ryb, Ryc and Ryd are each independently selected from H or C1-4 alkyl, preferably H, methyl or ethyl;
q is selected from 1 to 10;
m1 is selected from 0, 1, 2 or 3; and
p is selected from 0, 1 or 2.
Y is selected from methyl, hydroxyethyl, —CH2OC(═O)(Ry3), —C(═O)(Ry3), —CH2OC(═O)(W4Ry3), —C(═O)(W4Ry3), —CH(CH3)OC(═O)(W4Ry3), —CH2OP(═O)(W2Ry4)(W3Ry5), —P(═O)(W2Ry4)(W3Ry5) or
W2 and W3 are each independently selected from NH or O;
W4 is selected from CHRy10 or O;
Ry3 is selected from amino, aminomethylene, isopropyl, t-butyl, (t-butoxycarbonyl)amino, (t-butoxycarbonyl)aminomethylene, pyrrolylalkyl, phenyl or pyridinyl, wherein the amino group, pyrrolylalkyl, phenyl and pyridinyl are optionally further substituted with 0 to 4 substituents selected from t-butoxycarbonyl, acetoxy, or benzyloxycarbonyl;
Ry4 and Ry5 are each independently selected from H, Na+, K+, ethyl, benzyl, —CH2OC(═O)C(CH3)3, —CH(CH3)OC(═O)CH(CH3)2, —CH2OC(═O)CH2CH3, —CH2C(═O)OCH2CH3 or —CH2OC(═O)OCH(CH3)2;
Ry6 and Ry7 form phenyl together with the atoms to which they are attached;
Ry10 is selected from H, methyl, isopropyl, sec-butyl, 2-methylpropyl or benzyl.
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) to afford a compound of general formula (I); wherein preferably conducting the Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) at −4° C. to 35° C., and allowing the reaction to proceed for 2 to 20 h under stirring, to afford a compound of general formula (I);
or
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b), and further removing R′ from the product of the reaction to afford a compound of general formula (I); wherein preferably conducting the Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) at −4° C. to 35° C., allowing the reaction to proceed for 2 to 20 h under stirring, and further removing R′ from the product of the reaction to afford a compound of general formula (I);
or
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b), and removing hydroxyl from the product of the reaction by a reducing agent, to afford a compound of general formula (I); wherein preferably conducting the Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) at −4° C. to 35° C., allowing the reaction to proceed for 2 to 20 h under stirring, and removing hydroxyl from the product of the reaction by a reducing agent, to afford a compound of general formula (I);
or
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b), removing R′ from the product of the reaction, and further removing hydroxyl therefrom by a reducing agent, to afford a compound of general formula (I); wherein preferably conducting the Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) at −4° C. to 35° C., allowing the reaction to proceed for 2 to 20 h under stirring, removing R′ from the product of the reaction, and further removing hydroxyl therefrom by a reducing agent, to afford a compound of general formula (I);
wherein R′ is selected from H, methyl, ethyl, benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, or t-butyl(dimethyl)silyl; R, R4, R5 and n have the same definitions as those for the compound of general formula (I); X is selected from F, Cl, Br or I;
or,
allowing a compound of general formula (I-c) to either undergo a Grignard reaction, or react with a compound of general formula (I-d) under the action of an organolithium reagent, and then removing R″ to afford a compound of general formula (I); wherein, preferably, allowing a compound of general formula (I-c) to either undergo a Grignard reaction at −4° C. to 35° C. for 2 to 20 h under stirring, or react with a compound of general formula (I-d) under the action of an organolithium reagent for 30 min to 8 h at −78° C. to −50° C., and then removing R″ to afford a compound of general formula (I);
or
allowing a compound of general formula (I-c) to either undergo a Grignard reaction, or react with a compound of general formula (I-d) under the action of an organolithium reagent, then removing R″ from the product thereof, and further removing hydroxyl therefrom by a reducing agent, to afford a compound of general formula (I); wherein, preferably, allowing a compound of general formula (I-c) to, either undergo a Grignard reaction at −4° C. to 35° C. for 2 to 20 h under stirring, or react with a compound of general formula (I-d) under the action of an organolithium reagent for 30 min to 8 h at −78° C. to −50° C., then removing R″ from the product thereof, and further removing hydroxyl therefrom by a reducing agent, to afford a compound of general formula (I);
or
allowing a compound of general formula (I-c) to either undergo a Grignard reaction, or react with a compound of general formula (I-d) under the action of an organolithium reagent, further alkylating the product thereof, and then removing R″ therefrom to afford a compound of general formula (I); wherein, preferably, allowing a compound of general formula (I-c) to, either undergo a Grignard reaction at −4° C. to 35° C. for 2 to 20 h under stirring, or react with a compound of general formula (I-d) under the action of an organolithium reagent for 30 min to 8 h at −78° C. to −50° C., further alkylating the product thereof, and then removing R″ therefrom to afford a compound of general formula (I);
wherein R″ is selected from, methyl, ethyl, benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, or t-butyl(dimethyl)silyl; R, R4, R5 and n have the same definitions as those for the compound of general formula (I).
wherein
allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to directly afford a compound of general formula (I-B); or
allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-B), and subjecting the intermediate to hydrolysis and then to an exchange reaction with a metal salt to afford a compound of general formula (I-B); or
allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-B), and allowing the intermediate to further react with a nucleophilic reagent under the action of an alkali to afford a compound of general formula (I-B);
or,
allowing a compound of general formula (I) and a compound of general formula (I-C) to undergo nucleophilic substitution to afford a compound of general formula (I-D); and then
-
- allowing the compound of general formula (I-D) and a compound of general formula (I-E) to undergo nucleophilic substitution under the action of an alkali to directly afford a compound of general formula (I-F); or
- allowing the compound of general formula (I-D) and a compound of general formula (I-E) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-F), and subjecting the intermediate to hydrolysis and then to an exchange reaction with a metal salt to afford a compound of general formula (I-F); or
- allowing the compound of general formula (I-D) and a compound of general formula (I-E) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-F), and allowing the intermediate to further react with an electrophilic reagent under the action of an alkali to afford a compound of general formula (I-F);
wherein, R18 or R19 is each independently selected from F, Cl, Br, I, C1-10 alkyl or C1-10 alkoxy, preferably F, Cl, Br, I, C1-6 alkyl or C1-6 alkoxy, and more preferably F, Cl, Br, I, C1-4 alkyl or C1-4 alkoxy;
R20, R21 and R22 are each independently selected from H, F, Cl, Br, I or C1-10 alkyl, preferably H, F, Cl, Br, I or C1-6 alkyl, and more preferably H, F, Cl, Br, I or C1-4 alkyl;
V is selected from F, Cl, Br, I; and
n, R, R4, R5 and R6 have the same definitions as those in general formula (I).
wherein n is an integer of 2 to about 1000, preferably 2 to about 500, more preferably 2 to about 250, more preferably 2 to about 125, even more preferably 2 to about 25.
The carbocyclic group may optionally be further substituted with 0 to 8 substituents selected from F, Cl, Br, I, ═O, hydroxyl, mercapto, —SR18a, nitro, cyano, amino, alkylamino, an amide group, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, a carbocyclic group, a heterocyclic group, carbocyclyloxy, heterocyclyloxy, carboxyl, or a carboxylic ester group, wherein R18a is defined as above. This definition applies to the carbocyclic groups used throughout this Description.
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at −4° C. to 35° C. under N2 protection, and allowing the reaction to proceed for 2 to 20 h under stirring, to afford a compound of general formula (I);
or
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at −4° C. to 35° C. under N2 protection, allowing the reaction to proceed for 2 to 20 h under stirring, and further removing the protecting group (R′) for the phenolic hydroxyl to afford a compound of general formula (I), wherein the de-protecting agent is selected from Pd/C, palladium hydroxide, Raney Ni, trifluoroacetic acid, hydrochloric acid, tetrabutylammonium fluoride, aluminum trifluoride, aluminum trichloride or boron trifluoride;
or
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at −4° C. to 35° C. under N2 protection, allowing the reaction to proceed for 2 to 20 h under stirring, and removing hydroxyl from the product of the reaction under a reducing condition, to afford a compound of general formula (I);
or
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at −4° C. to 35° C. under N2 protection, allowing the reaction to proceed for 2 to 20 h under stirring, removing the protecting group (R′) for the phenolic hydroxyl, and further removing hydroxyl therefrom under a reducing condition, to afford a compound of general formula (I), wherein the reducing condition is selected from triethylsilane/trifluoroacetic acid, Pd/C, trimethylsilane chloride/sodium iodide, or carbon disulfide/sodium hydride;
X is selected from F, Cl, Br or I; R, R4, R5 and n have the same definitions as those for the compound of general formula (I); and R′ is defined as above;
or,
allowing a compound of general formula (I-c) to react with Mg in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at −4° C. to 35° C. under N2 protection to produce a Grignard reagent, allowing the Grignard reagent and a compound of general formula (I-d) to undergo a Grignard reaction for 2 to 20 h under stirring, and then removing the protecting group (R″) for the phenolic hydroxyl to afford a compound of general formula (I), wherein the de-protecting agent is as described above;
or
allowing a compound of general formula (I-c) to react with a compound of general formula (I-d) for 30 min to 8 h under the action of an organolithium reagent in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at −78° C. to −50° C. under N2 protection, and then removing the protecting group (R″) for the phenolic hydroxyl to afford a compound of general formula (I), wherein the organolithium reagent is selected from n-butyllithium, t-butyllithium, phenyllithium; diisopropylaminolithium or lithium hexamethyldisilylamide, and the de-protecting agent is as described above;
or
allowing a compound of general formula (I-c) to react with a compound of general formula (I-d) for 30 min to 8 h under the action of an organolithium reagent in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at −78° C. to −50° C. under N2 protection, then removing the protecting group (R″) for the phenolic hydroxyl, and further removing hydroxyl therefrom under a reducing condition, to afford a compound of general formula (I); wherein the reducing condition includes triethylsilane/trifluoroacetic acid, Pd/C, trimethylsilane chloride/sodium iodide, or carbon disulfide/sodium hydride, and the organolithium reagent, the reducing agent, and the de-protecting agent are as described above;
or
allowing a compound of general formula (I-c) and a compound of general formula (I-d) to undergo a Grignard reaction for 2 to 20 h under stirring in a solvent of tetrahydrofuran, toluene, ethyl ether, or methyl t-butyl ether at −4° C. to 35° C. under N2 protection, then to react with an alkylating agent, and further removing the protecting group (R″) for the phenolic hydroxyl to afford a compound of general formula (I); wherein the de-protecting agent is as described above;
or
allowing a compound of general formula (I-c) to react with a compound of general formula (I-d) for 30 min to 8 h under the action of an organolithium reagent at −78° C. to −50° C., allowing the product thereof to further react with an alkylating agent in the presence of sodium hydride or potassium t-butoxide, and then removing the protecting group (R″) for the phenolic hydroxyl therefrom to afford a compound of general formula (I); wherein the alkylating agent is selected from iodomethane, methyl p-toluenesulfonate, dimethyl sulfate, bromoethane, ethyl p-toluenesulfonate or diethyl sulfate, and the organolithium reagent, the reducing agent, and the de-protecting agent are as described above;
wherein R, R4, R5 and n have the same definitions as those for the compound of general formula (I); and R″ is defined as above.
wherein, R18 or R19 is each independently selected from F, Cl, Br, I, C1-10 alkyl or C1-10 alkoxy; V is selected from F, Cl, Br, I; and n, R, R4, R5 and R6 have the same definitions as those in general formula (I);
allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to directly afford a compound of general formula (I-B); or
allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-B), and subjecting the intermediate to hydrolysis and then to an exchange reaction with a metal salt to afford a compound of general formula (I-B); or
allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-B), and allowing the intermediate to further react with a nucleophilic reagent under the action of an alkali to afford a compound of general formula (I-B);
in step 1) above, (I-b) is a halophosphoryl-based compound, wherein R18 or R19 is selected from F, Cl, Br, I, C1-10 alkyl or C1-10 alkoxy; the alkali includes inorganic or organic alkali, preferably triethylamine, diisopropylethylamine or sodium hydride; the reaction temperature selected is −80° C. to 150° C.; and the reaction duration is 5 min to 2 days;
in step 2) above, the metal salt is an organic or inorganic salt of metal, preferably an alkali metal salt or alkali earth metal salt; the alkali includes inorganic or organic alkali, preferably triethylamine, diisopropylethylamine or sodium hydride; the reaction temperature selected is −80° C. to 150° C.; and the reaction duration is 5 min to 2 days;
or,
wherein, R20, R21 and R22 are each independently selected from H, F, Cl, Br, I or C1-10 alkyl; V is selected from F, Cl, Br, I; and n, R, R4, R5 and R6 have the same definitions as those in general formula (I);
allowing a compound of general formula (I) and a compound of general formula (I-C) to undergo nucleophilic substitution to afford a compound of general formula (I-D); and then
-
- allowing the compound of general formula (I-D) and a compound of general formula (I-E) to undergo nucleophilic substitution under the action of an alkali to directly afford a compound of general formula (I-F); or
- allowing the compound of general formula (I-D) and a compound of general formula (I-E) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-F), and subjecting the intermediate to hydrolysis and then to an exchange reaction with a metal salt to afford a compound of general formula (I-F); or
- allowing the compound of general formula (I-D) and a compound of general formula (I-E) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-F), and allowing the intermediate to further react with an electrophilic reagent under the action of an alkali to afford a compound of general formula (I-F);
in step 1) above, (I-C) is preferably a compound double-substituted with a halogen, V is preferable F, Cl, Br, or I; the preferred reaction temperature is 0° C. to 150° C.; and the preferred reaction duration is 0.5 to 12 h;
in step 2) above, (I-E) is a phosphate-based compound, wherein R21 and R22 are preferably H, F, Cl, Br, I or C1-10 alkyl; the alkali includes inorganic or organic alkali, preferably triethylamine, diisopropylethylamine or sodium hydride; the reaction temperature selected is −50° C. to 150° C.; and the reaction duration is 5 min to 2 days; in step 3) above, the metal salt is an organic or inorganic salt of metal, preferably an alkali metal salt or alkali earth metal salt; the alkali includes inorganic or organic alkali, preferably triethylamine, diisopropylethylamine or sodium hydride; the reaction temperature selected is −80° C. to 150° C.; and the reaction duration is 5 min to 2 days.
TABLE 1 |
Data from righting reflex experiment on mice |
Anes- | |||||||
Anes- | thesia | ||||||
Com- | thesia | main- | |||||
pound | ED50 | LD50 | induction | tenance | MTD | ||
No. | (mg/kg) | (mg/kg) | TI | SI | time (s) | time (s) | (mg/kg) |
Propofol | 11.7 | 31.3 | 2.7 | 1.5 | <15.0 s | 652.5 | 20.0 |
3 | 3.7 | 22.7 | 6.1 | 1.7 | <15.0 s | 660.4 | 10.0 |
4 | 4.5 | 38.1 | 8.4 | 2.6 | <15.0 s | 901.7 | 25.0 |
5 | 14.5 | 80.0 | 5.5 | 4.0 | <15.0 s | 1669.5 | 60.0 |
6 | 10.5 | 40.0 | 3.8 | 2.7 | <15.0 s | 554.9 | 30.0 |
7 | 7.1 | 40.0 | 5.7 | 2.7 | <15.0 s | 958.0 | 30.0 |
8 | 7.3 | 67.0 | 9.1 | 7.0 | <15.0 s | 394.8 | 40.0 |
11 | 30.1 | 100.0 | 3.3 | 2.5 | <15.0 s | 1494.7 | 80.0 |
13 | 3.6 | 20.0 | 5.5 | 3.0 | <15.0 s | 554.4 | 10.0 |
14 | 6.6 | 38.2 | 5.8 | 3.7 | <15.0 s | 2235.6 | 35.0 |
15 | 46.1 | 107.3 | 2.3 | 1.1 | <15.0 s | 485.8 | 70.0 |
16 | 1.5 | 9.9 | 6.7 | 4.1 | <15.0 s | 631.9 | 6.0 |
18 | 5.8 | 43.6 | 7.5 | 3.5 | <15.0 s | 1031.6 | 20.0 |
19 | 1.5 | 6.3 | 4.1 | 3.8 | <15.0 s | 754.4 | 5.0 |
20 | 15.7 | 150.0 | 9.6 | 4.4 | <15.0 s | 1207.7 | 90.0 |
25 | 2.0 | 14.3 | 7.1 | 4.6 | <15.0 s | 1048.0 | 10.0 |
26 | 1.3 | 8.3 | 6.4 | 2.4 | <15.0 s | 690.0 | 4.0 |
28 | 5.3 | 36.8 | 6.9 | 3.0 | <15.0 s | 885.9 | 15.0 |
29 | 10.1 | 65.4 | 6.4 | 3.7 | <15.0 s | 1149.5 | 40.0 |
TABLE 2 |
Comparison of HD7 between the testing compounds and propofol. |
Compound No. | HD7 (mg/kg) | ||
Propofol | 14.0 | ||
3 | 6.0 | ||
4 | 4.0 | ||
13 | 7.0 | ||
16 | 3.5 | ||
18 | 2.5 | ||
25 | 4.0 | ||
26 | 2.5 | ||
28 | 8.0 | ||
TABLE 3 |
Results of pharmacokinetic experiment on rats |
Intravenous Injection into Rats (1 mg/kg) |
AUC0→t | |||
Compound No. | (ng * h/mL) | t1/2 (h) | CL (mL/kg/min) |
Propofol | 81.9 | 0.7 | 204.0 |
8 | 132.0 | 0.8 | 119.0 |
13 | 187.0 | 0.2 | 87.5 |
16 | 168.0 | 0.5 | 105.0 |
25 | 78.1 | 0.4 | 208.0 |
26 | 124.0 | 0.5 | 134.0 |
28 | 143.0 | 0.3 | 115.0 |
29 | 114.0 | 0.4 | 145.0 |
TABLE 4 |
Data from pharmacokinetic experiment on rats with prodrugs. |
Intravenous Injection into Rats (10 mg/kg) |
Compound | AUC0→t | CL | ||
No. | Types | (ng * h/mL) | t1/2 (h) | (mL/kg/min) |
Propofol | — | 81.9 | 0.7 | 204.0 |
46 | prodrug | 22437.0 | 0.9 | 6.1 |
active form | 39.7 | 0.7 | NA | |
released upon | ||||
hydrolysis | ||||
52 | prodrug | 15946.0 | 0.4 | 10.5 |
active form | 606.0 | 0.5 | NA | |
released upon | ||||
hydrolysis | ||||
TABLE 5 |
Data from righting reflex experiment on mice with prodrugs |
Anes- | |||||||
Anes- | thesia | ||||||
Com- | thesia | main- | |||||
pound | ED50 | LD50 | induction | tenance | MTD | ||
No. | (mg/kg) | (mg/kg) | TI | SI | time (s) | time (s) | (mg/kg) |
Propofol | 11.7 | 31.3 | 2.7 | 1.5 | <15.0 | 652.5 | 20.0 |
35 | 39.3 | 200.0 | 5.1 | 4.9 | <15.0 | 1915.5 | 200.0 |
38 | 26.1 | 80.0 | 3.1 | 1.3 | 141.0 | 478.9 | 50.0 |
45 | 18.6 | 72.6 | 3.9 | 1.7 | 50.0 | 1716.0 | 50.0 |
46 | 72.6 | 225.0 | 3.1 | 2.4 | 167.0 | 2204.6 | 200.0 |
51 | 28.3 | 80.0 | 2.8 | 1.2 | 159.0 | 1159.9 | 40.0 |
52 | 20.4 | 86.2 | 4.2 | 3.3 | 73.0 | 1830.2 | 60.0 |
57 | 36.7 | 120.0 | 3.3 | 1.3 | 135.8 | 1931.2 | 80.0 |
60 | 13.8 | 79.6 | 5.8 | 3.1 | 6.0 | 1473.0 | 50.0 |
61 | 6.1 | 87.4 | 14.4 | 3.7 | 17.5 | 1109.2 | 40.0 |
62 | 7.7 | 45.6 | 5.9 | 1.6 | <15.0 | 696.9 | 30.0 |
65 | 82.7 | 369.8 | 4.5 | 2.9 | 82.5 | 3278.0 | 200.0 |
74 | 48.3 | 192.0 | 4.0 | 2.5 | 96.5 | 2378.3 | 120.0 |
75 | 11.7 | 42.4 | 3.6 | 2.3 | 129.2 | 2070.4 | 30.0 |
76 | 35.8 | 142.8 | 4.0 | 2.5 | 111.8 | 1992.8 | 80.0 |
77 | 94.7 | 274.3 | 2.9 | 1.7 | 175.4 | 1859.1 | 160.0 |
78 | 15.9 | 63.7 | 4.0 | 2.9 | 65.2 | 2634.6 | 40.0 |
79 | 24.3 | 91.8 | 3.8 | 2.1 | 72.5 | 2252.1 | 60.0 |
TABLE 6 |
Results of efficacy evaluation for rats |
Anes- | |||||||
Anes- | thesia | ||||||
Com- | thesia | main- | |||||
pound | ED50 | LD50 | induction | tenance | MTD | ||
No. | (mg/kg) | (mg/kg) | TI | SI | time (s) | time (s) | (mg/kg) |
Propofol | 5.7 | 19.1 | 3.4 | 1.5 | 0.0 | 652.0 | 12.5 |
52 | 12.5- | 61.4 | 4.1- | — | 92.8 | 1946.3 | 30.0 |
15.0 | 4.9 | ||||||
61 | 6.5 | 60.8 | 9.4 | 6.3 | 0.0 | 1474.9 | 40.0 |
Enhancement (%)=100*(Test Compound−Control)/Control
TABLE 7 |
Receptor patch-clamp experimental results. |
| Propofol | Compound | 16 |
EC50 (μM) | 5.3 | 1.1 | |
TABLE 8 |
Experimental results of aqueous phase concentration of free |
API of the compounds. |
Aqueous phase | |
Compound | concentration of free API |
Lipid emulsion of propofol (10 mg/mL) | 2.7 ug/mL |
Lipid emulsion of |
0.7 ug/mL |
(10 mg/mL) | |
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TWI617541B (en) * | 2015-05-28 | 2018-03-11 | Method for preparing 1,2-dicyclopropylethylphenol and optical isomers thereof | |
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JP7486438B2 (en) * | 2018-06-15 | 2024-05-17 | ファーマシェン エス.エー. | Novel process for the preparation of tapentadol |
CN113105313A (en) * | 2020-01-11 | 2021-07-13 | 四川海思科制药有限公司 | Phenol derivative and medical application thereof |
US20240132445A1 (en) | 2021-01-28 | 2024-04-25 | Hinye Pharmaceutical Co., Ltd. | Phenol derivative and application thereof in medicaments |
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